diff --git a/monai/data/image_reader.py b/monai/data/image_reader.py
index 27ac4d8287..53fcaa9545 100644
--- a/monai/data/image_reader.py
+++ b/monai/data/image_reader.py
@@ -347,6 +347,7 @@ def _get_affine(self, img, lps_to_ras: bool = True):
         affine: np.ndarray = np.eye(sr + 1)
         affine[:sr, :sr] = direction[:sr, :sr] @ np.diag(spacing[:sr])
         affine[:sr, -1] = origin[:sr]
+
         if lps_to_ras:
             affine = orientation_ras_lps(affine)
         return affine
@@ -752,13 +753,25 @@ def _get_affine(self, metadata: dict, lps_to_ras: bool = True):
                 stacklevel=2,
             )
             return affine
+
+        def _raise_if_not_finite(values: Sequence[Any], tag: str) -> None:
+            if not np.isfinite(tuple(values)).all():
+                raise ValueError(
+                    f"PydicomReader: cannot derive affine matrix because DICOM tag {tag} "
+                    f"has a non-finite value: {values}."
+                )
+
         # "00200037" is the tag of `ImageOrientationPatient`
         rx, ry, rz, cx, cy, cz = metadata["00200037"]["Value"]
+        _raise_if_not_finite((rx, ry, rz, cx, cy, cz), "ImageOrientationPatient (0020,0037)")
         # "00200032" is the tag of `ImagePositionPatient`
         sx, sy, sz = metadata["00200032"]["Value"]
+        _raise_if_not_finite((sx, sy, sz), "ImagePositionPatient (0020,0032)")
         # "00280030" is the tag of `PixelSpacing`
         spacing = metadata["00280030"]["Value"] if "00280030" in metadata else (1.0, 1.0)
+        _raise_if_not_finite(tuple(spacing), "PixelSpacing (0028,0030)")
         dr, dc = metadata.get("spacing", spacing)[:2]
+        _raise_if_not_finite((dr, dc), "spacing")
         affine[0, 0] = cx * dr
         affine[0, 1] = rx * dc
         affine[0, 3] = sx
@@ -773,12 +786,16 @@ def _get_affine(self, metadata: dict, lps_to_ras: bool = True):
         # 3d
         if "lastImagePositionPatient" in metadata:
             t1n, t2n, t3n = metadata["lastImagePositionPatient"]
+            _raise_if_not_finite((t1n, t2n, t3n), "lastImagePositionPatient")
             n = metadata[MetaKeys.SPATIAL_SHAPE][-1]
             if n > 1:
                 affine[0, 2] = (t1n - sx) / (n - 1)
                 affine[1, 2] = (t2n - sy) / (n - 1)
                 affine[2, 2] = (t3n - sz) / (n - 1)
 
+        if not np.isfinite(affine).all():
+            raise ValueError("PydicomReader: affine matrix not finite after composition.")
+
         if lps_to_ras:
             affine = orientation_ras_lps(affine)
         return affine
diff --git a/tests/data/test_pydicom_reader.py b/tests/data/test_pydicom_reader.py
index 1e55ee7a4e..42fcd89185 100644
--- a/tests/data/test_pydicom_reader.py
+++ b/tests/data/test_pydicom_reader.py
@@ -16,6 +16,7 @@
 import numpy as np
 
 from monai.data import PydicomReader
+from monai.utils import MetaKeys
 from tests.test_utils import SkipIfNoModule
 
 
@@ -39,6 +40,73 @@ def test_partial_orientation_tags_warns(self):
             affine = reader._get_affine(metadata)
         np.testing.assert_array_equal(affine, np.eye(4))
 
+    def test_non_finite_pixel_spacing_raises(self):
+        reader = PydicomReader()
+        metadata = {
+            "00200037": {"Value": [1.0, 0.0, 0.0, 0.0, 1.0, 0.0]},
+            "00200032": {"Value": [0.0, 0.0, 0.0]},
+            "00280030": {"Value": [np.nan, 1.0]},
+        }
+        with self.assertRaisesRegex(ValueError, "PixelSpacing"):
+            reader._get_affine(metadata, lps_to_ras=False)
+
+    def test_non_finite_image_position_raises(self):
+        reader = PydicomReader()
+        metadata = {
+            "00200037": {"Value": [1.0, 0.0, 0.0, 0.0, 1.0, 0.0]},
+            "00200032": {"Value": [np.inf, 0.0, 0.0]},
+            "00280030": {"Value": [1.0, 1.0]},
+        }
+        with self.assertRaisesRegex(ValueError, "ImagePositionPatient"):
+            reader._get_affine(metadata, lps_to_ras=False)
+
+    def test_finite_values_return_affine(self):
+        reader = PydicomReader()
+        metadata = {
+            "00200037": {"Value": [1.0, 0.0, 0.0, 0.0, 1.0, 0.0]},
+            "00200032": {"Value": [10.0, 20.0, 30.0]},
+            "00280030": {"Value": [0.5, 0.25]},
+        }
+        affine = reader._get_affine(metadata, lps_to_ras=False)
+        self.assertEqual(affine.shape, (4, 4))
+        self.assertTrue(np.all(np.isfinite(affine)))
+        np.testing.assert_allclose(affine[0, 3], 10.0)
+        np.testing.assert_allclose(affine[1, 3], 20.0)
+        np.testing.assert_allclose(affine[2, 3], 30.0)
+
+    def test_non_finite_orientation_raises(self):
+        reader = PydicomReader()
+        metadata = {
+            "00200037": {"Value": [np.nan, 0.0, 0.0, 0.0, 1.0, 0.0]},
+            "00200032": {"Value": [0.0, 0.0, 0.0]},
+            "00280030": {"Value": [1.0, 1.0]},
+        }
+        with self.assertRaisesRegex(ValueError, "ImageOrientationPatient"):
+            reader._get_affine(metadata, lps_to_ras=False)
+
+    def test_non_finite_last_image_position_raises(self):
+        reader = PydicomReader()
+        metadata = {
+            "00200037": {"Value": [1.0, 0.0, 0.0, 0.0, 1.0, 0.0]},
+            "00200032": {"Value": [0.0, 0.0, 0.0]},
+            "00280030": {"Value": [1.0, 1.0]},
+            "lastImagePositionPatient": [0.0, 0.0, np.inf],
+            MetaKeys.SPATIAL_SHAPE: [1, 1, 2],
+        }
+        with self.assertRaisesRegex(ValueError, "lastImagePositionPatient"):
+            reader._get_affine(metadata, lps_to_ras=False)
+
+    def test_overflow_from_finite_inputs_raises(self):
+        # Finite inputs whose product overflows produce a non-finite affine.
+        reader = PydicomReader()
+        metadata = {
+            "00200037": {"Value": [1e308, 0.0, 0.0, 1e308, 0.0, 0.0]},
+            "00200032": {"Value": [0.0, 0.0, 0.0]},
+            "00280030": {"Value": [1e308, 1e308]},
+        }
+        with self.assertRaisesRegex(ValueError, "not finite"):
+            reader._get_affine(metadata, lps_to_ras=False)
+
 
 if __name__ == "__main__":
     unittest.main()