diff --git a/changelog.d/3206.change.rst b/changelog.d/3206.change.rst
new file mode 100644
index 0000000000..f4d8683942
--- /dev/null
+++ b/changelog.d/3206.change.rst
@@ -0,0 +1,4 @@
+Fixed behaviour when both ``install_requires`` (in ``setup.py``) and
+``dependencies`` (in ``pyproject.toml``) are specified.
+The configuration in ``pyproject.toml`` will take precedence over ``setup.py``
+(in accordance with PEP 621). A warning was added to inform users.
diff --git a/setuptools/config/_apply_pyprojecttoml.py b/setuptools/config/_apply_pyprojecttoml.py
index a580b63f6f..002cc4b809 100644
--- a/setuptools/config/_apply_pyprojecttoml.py
+++ b/setuptools/config/_apply_pyprojecttoml.py
@@ -181,8 +181,10 @@ def _python_requires(dist: "Distribution", val: dict, _root_dir):
 
 
 def _dependencies(dist: "Distribution", val: list, _root_dir):
-    existing = getattr(dist, "install_requires", [])
-    _set_config(dist, "install_requires", existing + val)
+    if getattr(dist, "install_requires", []):
+        msg = "`install_requires` overwritten in `pyproject.toml` (dependencies)"
+        warnings.warn(msg)
+    _set_config(dist, "install_requires", val)
 
 
 def _optional_dependencies(dist: "Distribution", val: dict, _root_dir):
diff --git a/setuptools/tests/config/test_apply_pyprojecttoml.py b/setuptools/tests/config/test_apply_pyprojecttoml.py
index 4f541697aa..28643f0caf 100644
--- a/setuptools/tests/config/test_apply_pyprojecttoml.py
+++ b/setuptools/tests/config/test_apply_pyprojecttoml.py
@@ -257,6 +257,15 @@ def test_listed_in_dynamic(self, tmp_path, attr, field, value):
         dist_value = _some_attrgetter(f"metadata.{attr}", attr)(dist)
         assert dist_value == value
 
+    def test_warning_overwritten_dependencies(self, tmp_path):
+        src = "[project]\nname='pkg'\nversion='0.1'\ndependencies=['click']\n"
+        pyproject = tmp_path / "pyproject.toml"
+        pyproject.write_text(src, encoding="utf-8")
+        dist = makedist(tmp_path, install_requires=["wheel"])
+        with pytest.warns(match="`install_requires` overwritten"):
+            dist = pyprojecttoml.apply_configuration(dist, pyproject)
+        assert "wheel" not in dist.install_requires
+
     def test_optional_dependencies_dont_remove_env_markers(self, tmp_path):
         """
         Internally setuptools converts dependencies with markers to "extras".