diff --git a/doc/source/whatsnew/v0.24.0.txt b/doc/source/whatsnew/v0.24.0.txt
index a1a0857fe6365..d4be2f60a9e7a 100644
--- a/doc/source/whatsnew/v0.24.0.txt
+++ b/doc/source/whatsnew/v0.24.0.txt
@@ -373,6 +373,22 @@ is the case with :attr:`Period.end_time`, for example
 
    p.end_time
 
+.. _whatsnew_0240.api_breaking.frame_to_dict_index_orient:
+
+Raise ValueError in ``DataFrame.to_dict(orient='index')``
+^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^
+
+Bug in :func:`DataFrame.to_dict` raises ``ValueError`` when used with 
+``orient='index'`` and a non-unique index instead of losing data (:issue:`22801`)
+
+.. ipython:: python
+    :okexcept:
+
+    df = pd.DataFrame({'a': [1, 2], 'b': [0.5, 0.75]}, index=['A', 'A'])
+    df
+    
+    df.to_dict(orient='index')
+
 .. _whatsnew_0240.api.datetimelike.normalize:
 
 Tick DateOffset Normalize Restrictions
diff --git a/pandas/core/frame.py b/pandas/core/frame.py
index 986fe347898f5..db05c4372583a 100644
--- a/pandas/core/frame.py
+++ b/pandas/core/frame.py
@@ -1225,6 +1225,10 @@ def to_dict(self, orient='dict', into=dict):
                            for k, v in zip(self.columns, np.atleast_1d(row)))
                     for row in self.values]
         elif orient.lower().startswith('i'):
+            if not self.index.is_unique:
+                raise ValueError(
+                    "DataFrame index must be unique for orient='index'."
+                )
             return into_c((t[0], dict(zip(self.columns, t[1:])))
                           for t in self.itertuples())
         else:
diff --git a/pandas/tests/frame/test_convert_to.py b/pandas/tests/frame/test_convert_to.py
index a0e23d256c25b..61fe9d12c173c 100644
--- a/pandas/tests/frame/test_convert_to.py
+++ b/pandas/tests/frame/test_convert_to.py
@@ -71,6 +71,12 @@ def test_to_dict_timestamp(self):
         tm.assert_dict_equal(test_data_mixed.to_dict(orient='split'),
                              expected_split_mixed)
 
+    def test_to_dict_index_not_unique_with_index_orient(self):
+        # GH22801
+        # Data loss when indexes are not unique. Raise ValueError.
+        df = DataFrame({'a': [1, 2], 'b': [0.5, 0.75]}, index=['A', 'A'])
+        pytest.raises(ValueError, df.to_dict, orient='index')
+
     def test_to_dict_invalid_orient(self):
         df = DataFrame({'A': [0, 1]})
         pytest.raises(ValueError, df.to_dict, orient='xinvalid')