diff --git a/doc/source/whatsnew/v0.24.0.txt b/doc/source/whatsnew/v0.24.0.txt
index cf12759c051fc..9a77e3accb3dc 100644
--- a/doc/source/whatsnew/v0.24.0.txt
+++ b/doc/source/whatsnew/v0.24.0.txt
@@ -711,7 +711,7 @@ Reshaping
 - Bug in :func:`get_dummies` with Unicode attributes in Python 2 (:issue:`22084`)
 - Bug in :meth:`DataFrame.replace` raises ``RecursionError`` when replacing empty lists (:issue:`22083`)
 - Bug in :meth:`Series.replace` and meth:`DataFrame.replace` when dict is used as the `to_replace` value and one key in the dict is is another key's value, the results were inconsistent between using integer key and using string key (:issue:`20656`)
--
+- Bug in :meth:`DataFrame.drop_duplicates` for empty ``DataFrame`` which incorrectly raises an error (:issue:`20516`)
 
 Build Changes
 ^^^^^^^^^^^^^
diff --git a/pandas/core/frame.py b/pandas/core/frame.py
index 78ad9728800d6..0e1463693a7fc 100644
--- a/pandas/core/frame.py
+++ b/pandas/core/frame.py
@@ -4335,6 +4335,9 @@ def drop_duplicates(self, subset=None, keep='first', inplace=False):
         -------
         deduplicated : DataFrame
         """
+        if self.empty:
+            return self.copy()
+
         inplace = validate_bool_kwarg(inplace, 'inplace')
         duplicated = self.duplicated(subset, keep=keep)
 
@@ -4369,6 +4372,9 @@ def duplicated(self, subset=None, keep='first'):
         from pandas.core.sorting import get_group_index
         from pandas._libs.hashtable import duplicated_int64, _SIZE_HINT_LIMIT
 
+        if self.empty:
+            return Series()
+
         def f(vals):
             labels, shape = algorithms.factorize(
                 vals, size_hint=min(len(self), _SIZE_HINT_LIMIT))
diff --git a/pandas/tests/frame/test_duplicates.py b/pandas/tests/frame/test_duplicates.py
index 940692ec5b46a..3478d66b919a6 100644
--- a/pandas/tests/frame/test_duplicates.py
+++ b/pandas/tests/frame/test_duplicates.py
@@ -263,6 +263,23 @@ def test_drop_duplicates_tuple():
     tm.assert_frame_equal(result, expected)
 
 
+@pytest.mark.parametrize('df', [
+    DataFrame(),
+    DataFrame(columns=[]),
+    DataFrame(columns=['A', 'B', 'C']),
+    DataFrame(index=[]),
+    DataFrame(index=['A', 'B', 'C'])
+])
+def test_drop_duplicates_empty(df):
+    # GH 20516
+    result = df.drop_duplicates()
+    tm.assert_frame_equal(result, df)
+
+    result = df.copy()
+    result.drop_duplicates(inplace=True)
+    tm.assert_frame_equal(result, df)
+
+
 def test_drop_duplicates_NA():
     # none
     df = DataFrame({'A': [None, None, 'foo', 'bar',