diff --git a/doc/source/whatsnew/v0.25.1.rst b/doc/source/whatsnew/v0.25.1.rst
index c80195af413f7..a4e792091cb4b 100644
--- a/doc/source/whatsnew/v0.25.1.rst
+++ b/doc/source/whatsnew/v0.25.1.rst
@@ -152,7 +152,7 @@ ExtensionArray
 
 Other
 ^^^^^
-
+- Bug in :meth:`Series.replace` and :meth:`DataFrame.replace` when replacing timezone-aware timestamps using a dict-like replacer (:issue:`27720`)
 -
 -
 -
diff --git a/pandas/core/generic.py b/pandas/core/generic.py
index 821c35e0cce2f..2b783e3e7aaf8 100644
--- a/pandas/core/generic.py
+++ b/pandas/core/generic.py
@@ -6658,9 +6658,8 @@ def replace(
         else:
 
             # need a non-zero len on all axes
-            for a in self._AXIS_ORDERS:
-                if not len(self._get_axis(a)):
-                    return self
+            if not self.size:
+                return self
 
             new_data = self._data
             if is_dict_like(to_replace):
diff --git a/pandas/core/internals/managers.py b/pandas/core/internals/managers.py
index 8956821740bf3..b2019e3e59dda 100644
--- a/pandas/core/internals/managers.py
+++ b/pandas/core/internals/managers.py
@@ -7,7 +7,7 @@
 
 import numpy as np
 
-from pandas._libs import internals as libinternals, lib
+from pandas._libs import Timedelta, Timestamp, internals as libinternals, lib
 from pandas.util._validators import validate_bool_kwarg
 
 from pandas.core.dtypes.cast import (
@@ -602,9 +602,10 @@ def comp(s, regex=False):
             """
             if isna(s):
                 return isna(values)
-            if hasattr(s, "asm8"):
+            if isinstance(s, (Timedelta, Timestamp)) and getattr(s, "tz", None) is None:
+
                 return _compare_or_regex_search(
-                    maybe_convert_objects(values), getattr(s, "asm8"), regex
+                    maybe_convert_objects(values), s.asm8, regex
                 )
             return _compare_or_regex_search(values, s, regex)
 
diff --git a/pandas/tests/indexing/test_coercion.py b/pandas/tests/indexing/test_coercion.py
index dea1d5114f1b9..ed80e249220fd 100644
--- a/pandas/tests/indexing/test_coercion.py
+++ b/pandas/tests/indexing/test_coercion.py
@@ -1029,22 +1029,20 @@ def test_replace_series(self, how, to_key, from_key):
 
         tm.assert_series_equal(result, exp)
 
-    # TODO(jbrockmendel) commented out to only have a single xfail printed
-    @pytest.mark.xfail(
-        reason="GH #18376, tzawareness-compat bug in BlockManager.replace_list"
+    @pytest.mark.parametrize("how", ["dict", "series"])
+    @pytest.mark.parametrize(
+        "to_key",
+        ["timedelta64[ns]", "bool", "object", "complex128", "float64", "int64"],
     )
-    # @pytest.mark.parametrize('how', ['dict', 'series'])
-    # @pytest.mark.parametrize('to_key', ['timedelta64[ns]', 'bool', 'object',
-    #                                     'complex128', 'float64', 'int64'])
-    # @pytest.mark.parametrize('from_key', ['datetime64[ns, UTC]',
-    #                                       'datetime64[ns, US/Eastern]'])
-    # def test_replace_series_datetime_tz(self, how, to_key, from_key):
-    def test_replace_series_datetime_tz(self):
+    @pytest.mark.parametrize(
+        "from_key", ["datetime64[ns, UTC]", "datetime64[ns, US/Eastern]"]
+    )
+    def test_replace_series_datetime_tz(self, how, to_key, from_key):
         how = "series"
         from_key = "datetime64[ns, US/Eastern]"
         to_key = "timedelta64[ns]"
 
-        index = pd.Index([3, 4], name="xxx")
+        index = pd.Index([3, 4], name="xyz")
         obj = pd.Series(self.rep[from_key], index=index, name="yyy")
         assert obj.dtype == from_key
 
@@ -1061,24 +1059,17 @@ def test_replace_series_datetime_tz(self):
 
         tm.assert_series_equal(result, exp)
 
-    # TODO(jreback) commented out to only have a single xfail printed
-    @pytest.mark.xfail(
-        reason="different tz, currently mask_missing raises SystemError", strict=False
+    @pytest.mark.parametrize("how", ["dict", "series"])
+    @pytest.mark.parametrize(
+        "to_key",
+        ["datetime64[ns]", "datetime64[ns, UTC]", "datetime64[ns, US/Eastern]"],
     )
-    # @pytest.mark.parametrize('how', ['dict', 'series'])
-    # @pytest.mark.parametrize('to_key', [
-    #    'datetime64[ns]', 'datetime64[ns, UTC]',
-    #    'datetime64[ns, US/Eastern]'])
-    # @pytest.mark.parametrize('from_key', [
-    #    'datetime64[ns]', 'datetime64[ns, UTC]',
-    #    'datetime64[ns, US/Eastern]'])
-    # def test_replace_series_datetime_datetime(self, how, to_key, from_key):
-    def test_replace_series_datetime_datetime(self):
-        how = "dict"
-        to_key = "datetime64[ns]"
-        from_key = "datetime64[ns]"
-
-        index = pd.Index([3, 4], name="xxx")
+    @pytest.mark.parametrize(
+        "from_key",
+        ["datetime64[ns]", "datetime64[ns, UTC]", "datetime64[ns, US/Eastern]"],
+    )
+    def test_replace_series_datetime_datetime(self, how, to_key, from_key):
+        index = pd.Index([3, 4], name="xyz")
         obj = pd.Series(self.rep[from_key], index=index, name="yyy")
         assert obj.dtype == from_key