diff --git a/news/6264.bugfix.rst b/news/6264.bugfix.rst
new file mode 100644
index 000000000..66554a473
--- /dev/null
+++ b/news/6264.bugfix.rst
@@ -0,0 +1 @@
+Fix build environment isolation on some system Pythons.
diff --git a/src/pip/_internal/build_env.py b/src/pip/_internal/build_env.py
index 6213eedd1..cc2b38bab 100644
--- a/src/pip/_internal/build_env.py
+++ b/src/pip/_internal/build_env.py
@@ -4,6 +4,7 @@
 import logging
 import os
 import pathlib
+import site
 import sys
 import textwrap
 from collections import OrderedDict
@@ -55,6 +56,26 @@ def get_runnable_pip() -> str:
     return os.fsdecode(source / "__pip-runner__.py")
 
 
+def _get_system_sitepackages() -> Set[str]:
+    """Get system site packages
+
+    Usually from site.getsitepackages,
+    but fallback on `get_purelib()/get_platlib()` if unavailable
+    (e.g. in a virtualenv created by virtualenv<20)
+
+    Returns normalized set of strings.
+    """
+    if hasattr(site, "getsitepackages"):
+        system_sites = site.getsitepackages()
+    else:
+        # virtualenv < 20 overwrites site.py without getsitepackages
+        # fallback on get_purelib/get_platlib.
+        # this is known to miss things, but shouldn't in the cases
+        # where getsitepackages() has been removed (inside a virtualenv)
+        system_sites = [get_purelib(), get_platlib()]
+    return {os.path.normcase(path) for path in system_sites}
+
+
 class BuildEnvironment:
     """Creates and manages an isolated environment to install build deps"""
 
@@ -75,9 +96,8 @@ class BuildEnvironment:
         # Customize site to:
         # - ensure .pth files are honored
         # - prevent access to system site packages
-        system_sites = {
-            os.path.normcase(site) for site in (get_purelib(), get_platlib())
-        }
+        system_sites = _get_system_sitepackages()
+
         self._site_dir = os.path.join(temp_dir.path, "site")
         if not os.path.exists(self._site_dir):
             os.mkdir(self._site_dir)
diff --git a/tests/functional/test_build_env.py b/tests/functional/test_build_env.py
index 437adb995..869e8ad92 100644
--- a/tests/functional/test_build_env.py
+++ b/tests/functional/test_build_env.py
@@ -4,7 +4,7 @@ from typing import Optional
 
 import pytest
 
-from pip._internal.build_env import BuildEnvironment
+from pip._internal.build_env import BuildEnvironment, _get_system_sitepackages
 from tests.lib import (
     PipTestEnvironment,
     TestPipResult,
@@ -226,6 +226,10 @@ def test_build_env_isolation(script: PipTestEnvironment) -> None:
     script.pip_install_local("-t", target, pkg_whl)
     script.environ["PYTHONPATH"] = target
 
+    system_sites = _get_system_sitepackages()
+    # there should always be something to exclude
+    assert system_sites
+
     run_with_build_env(
         script,
         "",
@@ -247,5 +251,14 @@ def test_build_env_isolation(script: PipTestEnvironment) -> None:
                     })), file=sys.stderr)
             print('sys.path:\n  ' + '\n  '.join(sys.path), file=sys.stderr)
             sys.exit(1)
+        """
+        f"""
+        # second check: direct check of exclusion of system site packages
+        import os
+
+        normalized_path = [os.path.normcase(path) for path in sys.path]
+        for system_path in {system_sites!r}:
+            assert system_path not in normalized_path, \
+            f"{{system_path}} found in {{normalized_path}}"
         """,
     )