diff --git a/doc/source/whatsnew/v0.25.1.rst b/doc/source/whatsnew/v0.25.1.rst
index dfa216b1db56e..823064949859f 100644
--- a/doc/source/whatsnew/v0.25.1.rst
+++ b/doc/source/whatsnew/v0.25.1.rst
@@ -105,7 +105,7 @@ I/O
 ^^^
 
 - Avoid calling ``S3File.s3`` when reading parquet, as this was removed in s3fs version 0.3.0 (:issue:`27756`)
--
+- Better error message when a negative header is passed in :func:`pandas.read_csv` (:issue:`27779`)
 -
 
 Plotting
diff --git a/pandas/io/parsers.py b/pandas/io/parsers.py
index f4b00b0aac5f7..a3ff837bc7f52 100755
--- a/pandas/io/parsers.py
+++ b/pandas/io/parsers.py
@@ -1393,6 +1393,10 @@ def __init__(self, kwds):
         if isinstance(self.header, (list, tuple, np.ndarray)):
             if not all(map(is_integer, self.header)):
                 raise ValueError("header must be integer or list of integers")
+            if any(i < 0 for i in self.header):
+                raise ValueError(
+                    "cannot specify multi-index header with negative integers"
+                )
             if kwds.get("usecols"):
                 raise ValueError(
                     "cannot specify usecols when specifying a multi-index header"
@@ -1419,6 +1423,13 @@ def __init__(self, kwds):
         elif self.header is not None and not is_integer(self.header):
             raise ValueError("header must be integer or list of integers")
 
+        # GH 27779
+        elif self.header is not None and self.header < 0:
+            raise ValueError(
+                "Passing negative integer to header is invalid. "
+                "For no header, use header=None instead"
+            )
+
         self._name_processed = False
 
         self._first_chunk = True
diff --git a/pandas/tests/io/parser/test_header.py b/pandas/tests/io/parser/test_header.py
index 99e0181741998..0ecd8be7ddc78 100644
--- a/pandas/tests/io/parser/test_header.py
+++ b/pandas/tests/io/parser/test_header.py
@@ -24,6 +24,35 @@ def test_read_with_bad_header(all_parsers):
         parser.read_csv(s, header=[10])
 
 
+def test_negative_header(all_parsers):
+    # see gh-27779
+    parser = all_parsers
+    data = """1,2,3,4,5
+6,7,8,9,10
+11,12,13,14,15
+"""
+    with pytest.raises(
+        ValueError,
+        match="Passing negative integer to header is invalid. "
+        "For no header, use header=None instead",
+    ):
+        parser.read_csv(StringIO(data), header=-1)
+
+
+@pytest.mark.parametrize("header", [([-1, 2, 4]), ([-5, 0])])
+def test_negative_multi_index_header(all_parsers, header):
+    # see gh-27779
+    parser = all_parsers
+    data = """1,2,3,4,5
+        6,7,8,9,10
+        11,12,13,14,15
+        """
+    with pytest.raises(
+        ValueError, match="cannot specify multi-index header with negative integers"
+    ):
+        parser.read_csv(StringIO(data), header=header)
+
+
 @pytest.mark.parametrize("header", [True, False])
 def test_bool_header_arg(all_parsers, header):
     # see gh-6114