diff --git a/mypy/modulefinder.py b/mypy/modulefinder.py
index 17f386e933c1..6cebd7db8bc0 100644
--- a/mypy/modulefinder.py
+++ b/mypy/modulefinder.py
@@ -18,7 +18,7 @@
 from mypy.fscache import FileSystemCache
 from mypy.options import Options
 from mypy.stubinfo import is_legacy_bundled_package
-from mypy import sitepkgs
+from mypy import pyinfo
 
 # Paths to be searched in find_module().
 SearchPaths = NamedTuple(
@@ -582,6 +582,27 @@ def default_lib_path(data_dir: str,
     return path
 
 
+@functools.lru_cache(maxsize=None)
+def get_prefixes(python_executable: Optional[str]) -> Tuple[str, str]:
+    """Get the sys.base_prefix and sys.prefix for the given python.
+
+    This runs a subprocess call to get the prefix paths of the given Python executable.
+    To avoid repeatedly calling a subprocess (which can be slow!) we
+    lru_cache the results.
+    """
+    if python_executable is None:
+        return '', ''
+    elif python_executable == sys.executable:
+        # Use running Python's package dirs
+        return pyinfo.getprefixes()
+    else:
+        # Use subprocess to get the package directory of given Python
+        # executable
+        return ast.literal_eval(
+            subprocess.check_output([python_executable, pyinfo.__file__, 'getprefixes'],
+            stderr=subprocess.PIPE).decode())
+
+
 @functools.lru_cache(maxsize=None)
 def get_site_packages_dirs(python_executable: Optional[str]) -> Tuple[List[str], List[str]]:
     """Find package directories for given python.
@@ -595,12 +616,12 @@ def get_site_packages_dirs(python_executable: Optional[str]) -> Tuple[List[str],
         return [], []
     elif python_executable == sys.executable:
         # Use running Python's package dirs
-        site_packages = sitepkgs.getsitepackages()
+        site_packages = pyinfo.getsitepackages()
     else:
         # Use subprocess to get the package directory of given Python
         # executable
         site_packages = ast.literal_eval(
-            subprocess.check_output([python_executable, sitepkgs.__file__],
+            subprocess.check_output([python_executable, pyinfo.__file__, 'getsitepackages'],
             stderr=subprocess.PIPE).decode())
     return expand_site_packages(site_packages)
 
@@ -736,6 +757,8 @@ def compute_search_paths(sources: List[BuildSource],
         mypypath = add_py2_mypypath_entries(mypypath)
 
     egg_dirs, site_packages = get_site_packages_dirs(options.python_executable)
+    base_prefix, prefix = get_prefixes(options.python_executable)
+    is_venv = base_prefix != prefix
     for site_dir in site_packages:
         assert site_dir not in lib_path
         if (site_dir in mypypath or
@@ -745,7 +768,7 @@ def compute_search_paths(sources: List[BuildSource],
             print("See https://mypy.readthedocs.io/en/stable/running_mypy.html"
                   "#how-mypy-handles-imports for more info", file=sys.stderr)
             sys.exit(1)
-        elif site_dir in python_path:
+        elif site_dir in python_path and (is_venv and not site_dir.startswith(prefix)):
             print("{} is in the PYTHONPATH. Please change directory"
                   " so it is not.".format(site_dir),
                   file=sys.stderr)
diff --git a/mypy/sitepkgs.py b/mypy/pyinfo.py
similarity index 62%
rename from mypy/sitepkgs.py
rename to mypy/pyinfo.py
index 79dd5d80fcf6..7da94e0a1fb9 100644
--- a/mypy/sitepkgs.py
+++ b/mypy/pyinfo.py
@@ -1,21 +1,25 @@
 from __future__ import print_function
-"""This file is used to find the site packages of a Python executable, which may be Python 2.
+"""Utilities to find the site and prefix information of a Python executable, which may be Python 2.
 
 This file MUST remain compatible with Python 2. Since we cannot make any assumptions about the
 Python being executed, this module should not use *any* dependencies outside of the standard
 library found in Python 2. This file is run each mypy run, so it should be kept as fast as
 possible.
 """
+import site
+import sys
 
 if __name__ == '__main__':
-    import sys
     sys.path = sys.path[1:]  # we don't want to pick up mypy.types
 
-import site
-
 MYPY = False
 if MYPY:
-    from typing import List
+    from typing import List, Tuple
+
+
+def getprefixes():
+    # type: () -> Tuple[str, str]
+    return sys.base_prefix, sys.prefix
 
 
 def getsitepackages():
@@ -29,4 +33,10 @@ def getsitepackages():
 
 
 if __name__ == '__main__':
-    print(repr(getsitepackages()))
+    if sys.argv[-1] == 'getsitepackages':
+        print(repr(getsitepackages()))
+    elif sys.argv[-1] == 'getprefixes':
+        print(repr(getprefixes()))
+    else:
+        print("ERROR: incorrect argument to pyinfo.py.", file=sys.stderr)
+        sys.exit(1)
diff --git a/setup.py b/setup.py
index 726229bea1fe..7bd5b20cbf2c 100644
--- a/setup.py
+++ b/setup.py
@@ -86,7 +86,7 @@ def run(self):
     MYPYC_BLACKLIST = tuple(os.path.join('mypy', x) for x in (
         # Need to be runnable as scripts
         '__main__.py',
-        'sitepkgs.py',
+        'pyinfo.py',
         os.path.join('dmypy', '__main__.py'),
 
         # Uses __getattr__/__setattr__
diff --git a/test-requirements.txt b/test-requirements.txt
index d80d127cc440..93300baaaa8e 100644
--- a/test-requirements.txt
+++ b/test-requirements.txt
@@ -2,16 +2,15 @@
 -r build-requirements.txt
 attrs>=18.0
 flake8>=3.8.1
-flake8-bugbear; python_version >= '3.5'
-flake8-pyi>=20.5; python_version >= '3.6'
+flake8-bugbear
+flake8-pyi>=20.5
 lxml>=4.4.0
 psutil>=4.0
 pytest>=6.2.0,<7.0.0
 pytest-xdist>=1.34.0,<2.0.0
 pytest-forked>=1.3.0,<2.0.0
 pytest-cov>=2.10.0,<3.0.0
-typing>=3.5.2; python_version < '3.5'
 py>=1.5.2
-virtualenv<16.7.11
+virtualenv>=20.6.0
 setuptools!=50
-importlib-metadata==0.20
+importlib-metadata>=4.6.1,<5.0.0