diff --git a/packages/google-cloud-compute/noxfile.py b/packages/google-cloud-compute/noxfile.py
index fb09e54a93f2..ff946ee14bf6 100644
--- a/packages/google-cloud-compute/noxfile.py
+++ b/packages/google-cloud-compute/noxfile.py
@@ -138,6 +138,11 @@ def system(session):
     )
     session.install("-e", ".")
 
+    # If mtls is enabled via environment variable
+    # GOOGLE_API_USE_CLIENT_CERTIFICATE, then pyopenssl is needed. Here we
+    # install it regardless.
+    session.install("pyopenssl")
+
     # Run py.test against the system tests.
     if system_test_exists:
         session.run("py.test", "--quiet", system_test_path, *session.posargs)
diff --git a/packages/google-cloud-compute/tests/system.py b/packages/google-cloud-compute/tests/system.py
new file mode 100644
index 000000000000..2a4191546d78
--- /dev/null
+++ b/packages/google-cloud-compute/tests/system.py
@@ -0,0 +1,33 @@
+# -*- coding: utf-8 -*-
+#
+# Copyright 2021 Google LLC
+#
+# Licensed under the Apache License, Version 2.0 (the "License");
+# you may not use this file except in compliance with the License.
+# You may obtain a copy of the License at
+#
+#     https://www.apache.org/licenses/LICENSE-2.0
+#
+# Unless required by applicable law or agreed to in writing, software
+# distributed under the License is distributed on an "AS IS" BASIS,
+# WITHOUT WARRANTIES OR CONDITIONS OF ANY KIND, either express or implied.
+# See the License for the specific language governing permissions and
+# limitations under the License.
+
+import os
+import pytest
+
+from google.cloud import compute
+
+
+@pytest.fixture(scope="session")
+def project_id():
+    return os.environ["PROJECT_ID"]
+
+
+def test_list_instances_not_throw_mtls(project_id):
+    client = compute.InstancesClient()
+
+    # For regular system testing, the following call should never throw.
+    # For mTLS testing, the call throws if mTLS is not properly configured.
+    client.list(project=project_id, zone="us-west1-a")