diff --git a/README.md b/README.md
index d09d4d6..66f650f 100644
--- a/README.md
+++ b/README.md
@@ -931,4 +931,104 @@ curl -I https://artifacts.example.com/v2/dockerhub/library/nginx/manifests/lates
 
 # Check what's stored in the cache
 curl https://artifacts.example.com/ | jq '.remotes'
-```
\ No newline at end of file
+```
+
+## Python Package Proxy with uv
+
+The `pypi` package type turns the artifact API into a caching PyPI proxy. Simple index pages (`/simple/{package}/`) are mutable and expire after `mutable_ttl`; package files (wheels, sdists, metadata) are immutable and cached forever. URLs in the simple index HTML are rewritten on the fly to point back through the proxy, so both the index lookup and the file download are served from cache.
+
+### remotes.yaml
+
+```yaml
+remotes:
+  pypi:
+    base_url: "https://pypi.org"
+    type: "remote"
+    package: "pypi"
+    pypi_files_url: "https://files.pythonhosted.org"  # host to rewrite in index HTML
+    pypi_files_remote: "pypi-files"                    # our proxy remote to replace it with
+    check_mutable_updates: true
+    cache:
+      immutable_ttl: 0
+      mutable_ttl: 600   # re-check simple indexes after 10 minutes
+
+  pypi-files:
+    base_url: "https://files.pythonhosted.org"
+    type: "remote"
+    package: "generic"
+    immutable_patterns:
+      - "packages/.*\\.whl$"
+      - "packages/.*\\.whl\\.metadata$"
+      - "packages/.*\\.tar\\.gz$"
+      - "packages/.*\\.zip$"
+      - "packages/.*\\.egg$"
+    cache:
+      immutable_ttl: 0   # package files are content-addressed — cache forever
+
+  # Self-hosted Gitea PyPI registry (index and files share the same base URL)
+  pypi-gitea:
+    base_url: "https://gitea.example.com/api/packages/myorg/pypi"
+    type: "remote"
+    package: "pypi"
+    # username: "your-gitea-username"
+    # password: "your-personal-access-token"  # needs package:read scope
+    pypi_files_url: "https://gitea.example.com/api/packages/myorg/pypi"
+    pypi_files_remote: "pypi-gitea"  # point back to itself — Gitea serves both index and files
+    check_mutable_updates: true
+    immutable_patterns:
+      - "files/.*\\.whl$"
+      - "files/.*\\.whl\\.metadata$"
+      - "files/.*\\.tar\\.gz$"
+      - "files/.*\\.zip$"
+      - "files/.*\\.egg$"
+    cache:
+      immutable_ttl: 0
+      mutable_ttl: 600
+```
+
+### Configuring uv system- or user-wide
+
+uv reads `uv.toml` from two locations outside any project, applied in order from broadest to narrowest scope:
+
+| Scope | Path (Linux/macOS) |
+|---|---|
+| System | `/etc/uv/uv.toml` |
+| User | `~/.config/uv/uv.toml` |
+
+Use these files to route **all** package installs on a machine through the proxy without touching individual projects or their `pyproject.toml`.
+
+**`/etc/uv/uv.toml`** — applies to every user on the host:
+
+```toml
+# Replace the default PyPI index with the caching proxy
+[[index]]
+url = "https://artifacts.example.com/api/v1/remote/pypi/simple"
+default = true
+
+# Optionally add a private index (searched alongside the default)
+[[index]]
+url = "https://artifacts.example.com/api/v1/remote/pypi-gitea/simple"
+name = "gitea"
+```
+
+**`~/.config/uv/uv.toml`** — same syntax, single-user scope:
+
+```toml
+[[index]]
+url = "https://artifacts.example.com/api/v1/remote/pypi/simple"
+default = true
+```
+
+Setting `default = true` replaces uv's built-in PyPI index. The first install of a package fetches it from upstream and populates the cache; every subsequent install — from any machine or fresh environment pointing at the same proxy — is served directly from S3.
+
+### How the rewriting works
+
+When uv requests the simple index for a package, the proxy:
+
+1. Fetches `https://pypi.org/simple/{package}/` (or returns a valid cached copy within `mutable_ttl`)
+2. Rewrites every `https://files.pythonhosted.org/...` href to `https://artifacts.example.com/api/v1/remote/pypi-files/...`
+3. Returns the rewritten HTML to uv
+
+uv then downloads wheels and `.whl.metadata` files via the rewritten URLs, which also pass through the proxy and are cached as immutable artifacts.
+
+For self-hosted registries like Gitea, both the index and file downloads share the same base URL. Setting `pypi_files_url` and `pypi_files_remote` to the same remote causes file links to be rewritten back through the same proxy entry.
\ No newline at end of file
diff --git a/remotes.yaml b/remotes.yaml
index d312461..127de7a 100644
--- a/remotes.yaml
+++ b/remotes.yaml
@@ -194,6 +194,55 @@ remotes:
       immutable_ttl: 0
       mutable_ttl: 300
 
+  pypi:
+    base_url: "https://pypi.org"
+    type: "remote"
+    package: "pypi"
+    description: "Python Package Index — simple repository API"
+    # pypi_files_url: the upstream host used in simple-index hrefs (default: files.pythonhosted.org)
+    # pypi_files_remote: our proxy remote that will serve those files (default: pypi-files)
+    pypi_files_url: "https://files.pythonhosted.org"
+    pypi_files_remote: "pypi-files"
+    check_mutable_updates: true
+    cache:
+      immutable_ttl: 0
+      mutable_ttl: 600  # Simple index pages refreshed after 10 minutes
+
+  pypi-gitea:
+    base_url: "https://gitea.example.com/api/packages/myorg/pypi"
+    type: "remote"
+    package: "pypi"
+    description: "Private Gitea PyPI registry"
+    # username: "your-gitea-username"
+    # password: "your-personal-access-token"  # needs package:read scope
+    # Files are served from the same Gitea instance — rewrite back to this same remote
+    pypi_files_url: "https://gitea.example.com/api/packages/myorg/pypi"
+    pypi_files_remote: "pypi-gitea"
+    check_mutable_updates: true
+    immutable_patterns:
+      - "files/.*\\.whl$"
+      - "files/.*\\.whl\\.metadata$"
+      - "files/.*\\.tar\\.gz$"
+      - "files/.*\\.zip$"
+      - "files/.*\\.egg$"
+    cache:
+      immutable_ttl: 0
+      mutable_ttl: 600
+
+  pypi-files:
+    base_url: "https://files.pythonhosted.org"
+    type: "remote"
+    package: "generic"
+    description: "Python Package Index — file storage (wheels, sdists)"
+    immutable_patterns:
+      - "packages/.*\\.whl$"
+      - "packages/.*\\.whl\\.metadata$"
+      - "packages/.*\\.tar\\.gz$"
+      - "packages/.*\\.zip$"
+      - "packages/.*\\.egg$"
+    cache:
+      immutable_ttl: 0  # Package files are content-addressed — cache forever
+
   local-generic:
     type: "local"
     package: "generic"
diff --git a/src/artifactapi/config.py b/src/artifactapi/config.py
index ef138f3..c08860b 100644
--- a/src/artifactapi/config.py
+++ b/src/artifactapi/config.py
@@ -18,6 +18,9 @@ _PACKAGE_MUTABLE_PATTERNS: dict[str, list[str]] = {
         r"/manifests/(?!sha256:)[^/]+$",
         r"/tags/list$",
     ],
+    "pypi": [
+        r"simple/",  # Per-package and top-level simple index pages
+    ],
     "generic": [],
 }
 
diff --git a/src/artifactapi/main.py b/src/artifactapi/main.py
index 148fc77..2f8fd1e 100644
--- a/src/artifactapi/main.py
+++ b/src/artifactapi/main.py
@@ -1,3 +1,4 @@
+import base64
 import hashlib
 import json
 import logging
@@ -208,8 +209,11 @@ async def cache_single_artifact(url: str, remote_name: str, path: str) -> dict:
         remote_config = config.get_remote_config(remote_name) or {}
         is_docker = remote_config.get("package") == "docker" or "/v2/" in url
 
-        # Prepare headers for Docker registry requests
+        # Prepare headers
         headers = {}
+        username = remote_config.get("username")
+        password = remote_config.get("password")
+
         if is_docker:
             if "/manifests/" in url:
                 headers["Accept"] = (
@@ -220,6 +224,8 @@ async def cache_single_artifact(url: str, remote_name: str, path: str) -> dict:
                 )
             elif "/blobs/" in url:
                 headers["Accept"] = "application/octet-stream"
+        elif username and password:
+            headers["Authorization"] = "Basic " + base64.b64encode(f"{username}:{password}".encode()).decode()
 
         async with httpx.AsyncClient(follow_redirects=True) as client:
             response = await client.get(url, headers=headers)
@@ -254,11 +260,20 @@ async def cache_single_artifact(url: str, remote_name: str, path: str) -> dict:
         return {"url": url, "status": "error", "error": str(e)}
 
 
-async def _upstream_reachable(url: str) -> bool:
+def _basic_auth_header(remote_cfg: dict) -> dict[str, str]:
+    username = remote_cfg.get("username")
+    password = remote_cfg.get("password")
+    if username and password:
+        token = base64.b64encode(f"{username}:{password}".encode()).decode()
+        return {"Authorization": f"Basic {token}"}
+    return {}
+
+
+async def _upstream_reachable(url: str, auth_headers: dict | None = None) -> bool:
     """HEAD with a short timeout. Returns False only on network/timeout errors."""
     try:
         async with httpx.AsyncClient(follow_redirects=True) as client:
-            await client.head(url, timeout=10.0)
+            await client.head(url, headers=auth_headers or {}, timeout=10.0)
         return True
     except (httpx.NetworkError, httpx.TimeoutException):
         return False
@@ -266,19 +281,19 @@ async def _upstream_reachable(url: str) -> bool:
         return True  # 4xx/5xx means backend is up
 
 
-async def check_upstream_changed(remote_url: str, remote_name: str, path: str) -> bool:
+async def check_upstream_changed(remote_url: str, remote_name: str, path: str, auth_headers: dict | None = None) -> bool:
     """Conditional HEAD against upstream. Returns False only on a definitive 304.
     Raises UpstreamUnreachable if the backend cannot be contacted."""
     meta = cache.get_mutable_meta(remote_name, path)
     if not meta:
         return True
 
-    headers = {}
+    headers = dict(auth_headers or {})
     if meta.get("etag"):
         headers["If-None-Match"] = meta["etag"]
     if meta.get("last_modified"):
         headers["If-Modified-Since"] = meta["last_modified"]
-    if not headers:
+    if not (meta.get("etag") or meta.get("last_modified")):
         return True
 
     try:
@@ -294,12 +309,13 @@ async def handle_expired_mutable(remote_name: str, path: str, remote_url: str) -
     mutable_ttl = config.get_cache_config(remote_name).get("mutable_ttl", 3600)
 
     remote_cfg = config.get_remote_config(remote_name) or {}
+    auth = _basic_auth_header(remote_cfg)
     check_updates = remote_cfg.get("check_mutable_updates", False)
     user_mutable = check_updates and cache.is_mutable_file(path, config.get_user_mutable_patterns(remote_name))
 
     if user_mutable:
         try:
-            changed = await check_upstream_changed(remote_url, remote_name, path)
+            changed = await check_upstream_changed(remote_url, remote_name, path, auth)
         except UpstreamUnreachable:
             cache.mark_index_cached(remote_name, path, mutable_ttl)
             logger.warning(f"Mutable STALE (backend unreachable): {remote_name}/{path} - TTL extended ({mutable_ttl}s)")
@@ -310,7 +326,7 @@ async def handle_expired_mutable(remote_name: str, path: str, remote_url: str) -
             return True
         logger.info(f"Mutable file CHANGED: {remote_name}/{path} - re-downloading")
     else:
-        if not await _upstream_reachable(remote_url):
+        if not await _upstream_reachable(remote_url, auth):
             cache.mark_index_cached(remote_name, path, mutable_ttl)
             logger.warning(f"Mutable STALE (backend unreachable): {remote_name}/{path} - TTL extended ({mutable_ttl}s)")
             return True
@@ -320,8 +336,44 @@ async def handle_expired_mutable(remote_name: str, path: str, remote_url: str) -
     return False
 
 
+def _get_content_type(filename: str) -> str:
+    if filename.endswith(".tar.gz"):
+        return "application/gzip"
+    if filename.endswith(".zip") or filename.endswith(".whl"):
+        return "application/zip"
+    if filename.endswith(".exe"):
+        return "application/x-msdownload"
+    if filename.endswith(".rpm"):
+        return "application/x-rpm"
+    if filename.endswith(".xml"):
+        return "application/xml"
+    if filename.endswith((".xml.gz", ".xml.bz2", ".xml.xz")):
+        return "application/gzip"
+    return "application/octet-stream"
+
+
+def _resolve_content(
+    data: bytes,
+    path: str,
+    filename: str,
+    remote_config: dict,
+    request: Request,
+) -> tuple[bytes, str]:
+    """Return (possibly-rewritten data, content_type) for a cached artifact."""
+    if remote_config.get("package") == "pypi" and "simple/" in path:
+        files_url = remote_config.get("pypi_files_url", "https://files.pythonhosted.org")
+        files_remote = remote_config.get("pypi_files_remote", "pypi-files")
+        proxy_base = str(request.base_url).rstrip("/")
+        data = data.replace(
+            files_url.rstrip("/").encode(),
+            f"{proxy_base}/api/v1/remote/{files_remote}".encode(),
+        )
+        return data, "text/html; charset=utf-8"
+    return data, _get_content_type(filename)
+
+
 @app.get("/api/v1/remote/{remote_name}/{path:path}")
-async def get_artifact(remote_name: str, path: str):
+async def get_artifact(request: Request, remote_name: str, path: str):
     # Check if remote is configured
     remote_config = config.get_remote_config(remote_name)
     if not remote_config:
@@ -384,29 +436,11 @@ async def get_artifact(remote_name: str, path: str):
         try:
             artifact_data = storage.download_object(cached_key)
             filename = os.path.basename(path)
+            artifact_data, content_type = _resolve_content(artifact_data, path, filename, remote_config, request)
 
-            # Log cache hit
             logger.info(f"Cache HIT: {remote_name}/{path} (size: {len(artifact_data)} bytes, key: {cached_key})")
 
-            # Determine content type based on file extension
-            content_type = "application/octet-stream"
-            if filename.endswith(".tar.gz"):
-                content_type = "application/gzip"
-            elif filename.endswith(".zip"):
-                content_type = "application/zip"
-            elif filename.endswith(".exe"):
-                content_type = "application/x-msdownload"
-            elif filename.endswith(".rpm"):
-                content_type = "application/x-rpm"
-            elif filename.endswith(".xml"):
-                content_type = "application/xml"
-            elif filename.endswith((".xml.gz", ".xml.bz2", ".xml.xz")):
-                content_type = "application/gzip"
-
-            # Record cache hit metrics
             metrics.record_cache_hit(remote_name, len(artifact_data))
-
-            # Record artifact mapping in database if not already recorded
             database.record_artifact_mapping(cached_key, remote_name, path, len(artifact_data))
 
             return Response(
@@ -443,25 +477,9 @@ async def get_artifact(remote_name: str, path: str):
         cache_key = storage.get_object_key(remote_name, path)
         artifact_data = storage.download_object(cache_key)
         filename = os.path.basename(path)
+        artifact_data, content_type = _resolve_content(artifact_data, path, filename, remote_config, request)
 
-        content_type = "application/octet-stream"
-        if filename.endswith(".tar.gz"):
-            content_type = "application/gzip"
-        elif filename.endswith(".zip"):
-            content_type = "application/zip"
-        elif filename.endswith(".exe"):
-            content_type = "application/x-msdownload"
-        elif filename.endswith(".rpm"):
-            content_type = "application/x-rpm"
-        elif filename.endswith(".xml"):
-            content_type = "application/xml"
-        elif filename.endswith((".xml.gz", ".xml.bz2", ".xml.xz")):
-            content_type = "application/gzip"
-
-        # Record cache miss metrics
         metrics.record_cache_miss(remote_name, len(artifact_data))
-
-        # Record artifact mapping in database
         cache_key = storage.get_object_key(remote_name, path)
         database.record_artifact_mapping(cache_key, remote_name, path, len(artifact_data))
 
diff --git a/tests/conftest.py b/tests/conftest.py
index 9326244..f46e0d4 100644
--- a/tests/conftest.py
+++ b/tests/conftest.py
@@ -72,6 +72,25 @@ TEST_REMOTES = {
             "package": "generic",
             "cache": {"immutable_ttl": 0, "mutable_ttl": 0},
         },
+        "pypi-test": {
+            "base_url": "https://pypi.org",
+            "type": "remote",
+            "package": "pypi",
+            "pypi_files_url": "https://files.pythonhosted.org",
+            "pypi_files_remote": "pypi-files-test",
+            "cache": {"immutable_ttl": 0, "mutable_ttl": 600},
+        },
+        "pypi-files-test": {
+            "base_url": "https://files.pythonhosted.org",
+            "type": "remote",
+            "package": "generic",
+            "immutable_patterns": [
+                "packages/.*\\.whl$",
+                "packages/.*\\.whl\\.metadata$",
+                "packages/.*\\.tar\\.gz$",
+            ],
+            "cache": {"immutable_ttl": 0, "mutable_ttl": 0},
+        },
     }
 }
 
diff --git a/tests/test_routes.py b/tests/test_routes.py
index d2dc643..9d8bdaa 100644
--- a/tests/test_routes.py
+++ b/tests/test_routes.py
@@ -652,3 +652,92 @@ class TestConfigEndpoint:
         data = response.json()
         assert "remotes" in data
         assert "alpine-test" in data["remotes"]
+
+
+# ---------------------------------------------------------------------------
+# PyPI remote  /api/v1/remote/pypi-test/...
+# ---------------------------------------------------------------------------
+
+
+class TestPyPIRemote:
+    def test_simple_index_is_mutable(self, client, patched_deps):
+        """simple/ paths are detected as mutable (package-type default)."""
+        deps = patched_deps
+        html = b"<html><body><a href='https://files.pythonhosted.org/packages/requests-2.31.0.tar.gz'>...</a></body></html>"
+        deps["storage"].exists.return_value = True
+        deps["storage"].download_object.return_value = html
+        deps["cache"].is_mutable_file.return_value = True
+        deps["cache"].is_index_valid.return_value = True
+
+        response = client.get("/api/v1/remote/pypi-test/simple/requests/")
+        assert response.status_code == 200
+        deps["cache"].mark_index_cached.assert_not_called()
+
+    def test_simple_index_urls_rewritten_to_proxy(self, client, patched_deps):
+        """files.pythonhosted.org URLs in a cached simple index are rewritten to our proxy."""
+        deps = patched_deps
+        html = b"<html><body><a href='https://files.pythonhosted.org/packages/requests-2.31.0.tar.gz'>...</a></body></html>"
+        deps["storage"].exists.return_value = True
+        deps["storage"].download_object.return_value = html
+        deps["cache"].is_mutable_file.return_value = True
+        deps["cache"].is_index_valid.return_value = True
+
+        response = client.get("/api/v1/remote/pypi-test/simple/requests/")
+        assert response.status_code == 200
+        assert b"files.pythonhosted.org" not in response.content
+        assert b"/api/v1/remote/pypi-files-test/packages/requests-2.31.0.tar.gz" in response.content
+
+    def test_simple_index_content_type_is_html(self, client, patched_deps):
+        deps = patched_deps
+        deps["storage"].exists.return_value = True
+        deps["storage"].download_object.return_value = b"<html></html>"
+        deps["cache"].is_mutable_file.return_value = True
+        deps["cache"].is_index_valid.return_value = True
+
+        response = client.get("/api/v1/remote/pypi-test/simple/requests/")
+        assert response.status_code == 200
+        assert "text/html" in response.headers["content-type"]
+
+    def test_simple_index_cache_miss_fetches_upstream(self, client, patched_deps):
+        deps = patched_deps
+        html = b"<html><body><a href='https://files.pythonhosted.org/packages/p-1.0.whl'>...</a></body></html>"
+        deps["storage"].exists.return_value = False
+        deps["storage"].download_object.return_value = html
+        deps["cache"].is_mutable_file.return_value = True
+
+        with patch(
+            "artifactapi.main.cache_single_artifact",
+            new_callable=AsyncMock,
+            return_value={"status": "cached"},
+        ) as mock_fetch:
+            response = client.get("/api/v1/remote/pypi-test/simple/requests/")
+
+        mock_fetch.assert_called_once()
+        assert response.status_code == 200
+        assert b"files.pythonhosted.org" not in response.content
+
+    def test_wheel_file_immutable_returns_correct_content_type(self, client, patched_deps):
+        deps = patched_deps
+        deps["storage"].exists.return_value = True
+        deps["storage"].download_object.return_value = b"PK wheel bytes"
+        deps["cache"].is_mutable_file.return_value = False
+
+        response = client.get("/api/v1/remote/pypi-files-test/packages/requests-2.31.0-py3-none-any.whl")
+        assert response.status_code == 200
+        assert "application/zip" in response.headers["content-type"]
+        assert response.headers["X-Artifact-Source"] == "cache"
+
+    def test_sdist_immutable_returns_correct_content_type(self, client, patched_deps):
+        deps = patched_deps
+        deps["storage"].exists.return_value = True
+        deps["storage"].download_object.return_value = b"tar bytes"
+        deps["cache"].is_mutable_file.return_value = False
+
+        response = client.get("/api/v1/remote/pypi-files-test/packages/requests-2.31.0.tar.gz")
+        assert response.status_code == 200
+        assert "application/gzip" in response.headers["content-type"]
+
+    def test_blocked_path_on_files_remote_returns_403(self, client, patched_deps):
+        """Paths that don't match immutable_patterns on pypi-files-test are blocked."""
+        response = client.get("/api/v1/remote/pypi-files-test/packages/requests.unknown")
+        assert response.status_code == 403