diff --git a/doc/source/whatsnew/v1.3.0.rst b/doc/source/whatsnew/v1.3.0.rst
index a4a589cef7b02..42c8a64890a16 100644
--- a/doc/source/whatsnew/v1.3.0.rst
+++ b/doc/source/whatsnew/v1.3.0.rst
@@ -681,6 +681,7 @@ Deprecations
 - Deprecated passing arguments as positional in :meth:`DataFrame.clip` and :meth:`Series.clip` (other than ``"upper"`` and ``"lower"``) (:issue:`41485`)
 - Deprecated special treatment of lists with first element a Categorical in the :class:`DataFrame` constructor; pass as ``pd.DataFrame({col: categorical, ...})`` instead (:issue:`38845`)
 - Deprecated passing arguments as positional (except for ``"method"``) in :meth:`DataFrame.interpolate` and :meth:`Series.interpolate` (:issue:`41485`)
+- Deprecated passing arguments as positional in :meth:`DataFrame.set_index` (other than ``"keys"``) (:issue:`41485`)
 - Deprecated passing arguments as positional (except for ``"levels"``) in :meth:`MultiIndex.set_levels` (:issue:`41485`)
 - Deprecated passing arguments as positional in :meth:`DataFrame.sort_index` and :meth:`Series.sort_index` (:issue:`41485`)
 - Deprecated passing arguments as positional in :meth:`DataFrame.drop_duplicates` (except for ``subset``), :meth:`Series.drop_duplicates`, :meth:`Index.drop_duplicates` and :meth:`MultiIndex.drop_duplicates`(:issue:`41485`)
diff --git a/pandas/core/frame.py b/pandas/core/frame.py
index 3742fb595d2cd..35b55f68d0240 100644
--- a/pandas/core/frame.py
+++ b/pandas/core/frame.py
@@ -5330,6 +5330,7 @@ def shift(
             periods=periods, freq=freq, axis=axis, fill_value=fill_value
         )
 
+    @deprecate_nonkeyword_arguments(version=None, allowed_args=["self", "keys"])
     def set_index(
         self,
         keys,
diff --git a/pandas/tests/frame/methods/test_set_index.py b/pandas/tests/frame/methods/test_set_index.py
index 51f66128b1500..1b3db10ec6158 100644
--- a/pandas/tests/frame/methods/test_set_index.py
+++ b/pandas/tests/frame/methods/test_set_index.py
@@ -704,3 +704,15 @@ def test_set_index_periodindex(self):
         tm.assert_index_equal(df.index, idx1)
         df = df.set_index(idx2)
         tm.assert_index_equal(df.index, idx2)
+
+    def test_drop_pos_args_deprecation(self):
+        # https://github.com/pandas-dev/pandas/issues/41485
+        df = DataFrame({"a": [1, 2, 3]})
+        msg = (
+            r"In a future version of pandas all arguments of DataFrame\.set_index "
+            r"except for the argument 'keys' will be keyword-only"
+        )
+        with tm.assert_produces_warning(FutureWarning, match=msg):
+            result = df.set_index("a", True)
+        expected = DataFrame(index=Index([1, 2, 3], name="a"))
+        tm.assert_frame_equal(result, expected)