diff --git a/pandas/core/frame.py b/pandas/core/frame.py
index 66d3800301f92..24517149f511a 100644
--- a/pandas/core/frame.py
+++ b/pandas/core/frame.py
@@ -3914,9 +3914,9 @@ def _set_item_mgr(self, key, value: ArrayLike) -> None:
         if len(self):
             self._check_setitem_copy()
 
-    def _iset_item(self, loc: int, value, inplace: bool = False) -> None:
+    def _iset_item(self, loc: int, value) -> None:
         arraylike = self._sanitize_column(value)
-        self._iset_item_mgr(loc, arraylike, inplace=inplace)
+        self._iset_item_mgr(loc, arraylike, inplace=True)
 
         # check if we are modifying a copy
         # try to set first as we want an invalid
diff --git a/pandas/core/indexing.py b/pandas/core/indexing.py
index b2e2bb0642c41..fc2204724aceb 100644
--- a/pandas/core/indexing.py
+++ b/pandas/core/indexing.py
@@ -1871,11 +1871,11 @@ def _setitem_single_column(self, loc: int, value, plane_indexer):
                 # The setitem happened inplace, so the DataFrame's values
                 #  were modified inplace.
                 return
-            self.obj._iset_item(loc, ser, inplace=True)
+            self.obj._iset_item(loc, ser)
             return
 
         # reset the sliced object if unique
-        self.obj._iset_item(loc, ser, inplace=True)
+        self.obj._iset_item(loc, ser)
 
     def _setitem_single_block(self, indexer, value, name: str):
         """
@@ -1892,19 +1892,15 @@ def _setitem_single_block(self, indexer, value, name: str):
             # set using those methods to avoid block-splitting
             # logic here
             if (
-                len(indexer) > info_axis
-                and is_integer(indexer[info_axis])
-                and all(
-                    com.is_null_slice(idx)
-                    for i, idx in enumerate(indexer)
-                    if i != info_axis
-                )
+                self.ndim == len(indexer) == 2
+                and is_integer(indexer[1])
+                and com.is_null_slice(indexer[0])
             ):
                 col = item_labels[indexer[info_axis]]
                 if len(item_labels.get_indexer_for([col])) == 1:
                     # e.g. test_loc_setitem_empty_append_expands_rows
                     loc = item_labels.get_loc(col)
-                    self.obj._iset_item(loc, value, inplace=True)
+                    self.obj._iset_item(loc, value)
                     return
 
             indexer = maybe_convert_ix(*indexer)  # e.g. test_setitem_frame_align