diff --git a/doc/source/whatsnew/v1.2.0.rst b/doc/source/whatsnew/v1.2.0.rst
index 260b92b5989c1..044226e7379bb 100644
--- a/doc/source/whatsnew/v1.2.0.rst
+++ b/doc/source/whatsnew/v1.2.0.rst
@@ -134,7 +134,7 @@ Missing
 MultiIndex
 ^^^^^^^^^^
 
--
+- Bug in :meth:`DataFrame.xs` when used with :class:`IndexSlice` raises ``TypeError`` with message `Expected label or tuple of labels` (:issue:`35301`)
 -
 
 I/O
diff --git a/pandas/core/generic.py b/pandas/core/generic.py
index 6fd55c58ece40..843b602a12823 100644
--- a/pandas/core/generic.py
+++ b/pandas/core/generic.py
@@ -3492,7 +3492,10 @@ class   animal   locomotion
 
         index = self.index
         if isinstance(index, MultiIndex):
-            loc, new_index = self.index.get_loc_level(key, drop_level=drop_level)
+            try:
+                loc, new_index = self.index.get_loc_level(key, drop_level=drop_level)
+            except TypeError as e:
+                raise TypeError(f"Expected label or tuple of labels, got {key}") from e
         else:
             loc = self.index.get_loc(key)
 
diff --git a/pandas/tests/indexing/multiindex/test_xs.py b/pandas/tests/indexing/multiindex/test_xs.py
index b807795b9c309..91be1d913001b 100644
--- a/pandas/tests/indexing/multiindex/test_xs.py
+++ b/pandas/tests/indexing/multiindex/test_xs.py
@@ -1,7 +1,7 @@
 import numpy as np
 import pytest
 
-from pandas import DataFrame, Index, MultiIndex, Series, concat, date_range
+from pandas import DataFrame, Index, IndexSlice, MultiIndex, Series, concat, date_range
 import pandas._testing as tm
 import pandas.core.common as com
 
@@ -220,6 +220,27 @@ def test_xs_level_series_slice_not_implemented(
         s[2000, 3:4]
 
 
+def test_xs_IndexSlice_argument_not_implemented():
+    # GH 35301
+
+    index = MultiIndex(
+        levels=[[("foo", "bar", 0), ("foo", "baz", 0), ("foo", "qux", 0)], [0, 1]],
+        codes=[[0, 0, 1, 1, 2, 2], [0, 1, 0, 1, 0, 1]],
+    )
+
+    series = Series(np.random.randn(6), index=index)
+    frame = DataFrame(np.random.randn(6, 4), index=index)
+
+    msg = (
+        "Expected label or tuple of labels, got "
+        r"\(\('foo', 'qux', 0\), slice\(None, None, None\)\)"
+    )
+    with pytest.raises(TypeError, match=msg):
+        frame.xs(IndexSlice[("foo", "qux", 0), :])
+    with pytest.raises(TypeError, match=msg):
+        series.xs(IndexSlice[("foo", "qux", 0), :])
+
+
 def test_series_getitem_multiindex_xs():
     # GH6258
     dt = list(date_range("20130903", periods=3))