The expression of transferrin receptors (TfR's) has been investigated in eight liver biopsy specimens (four from patients without demonstrable iron and four from patients with iron storage due to primary hemochromatosis (HC)) using immunoelectron microscopy to demonstrate TfR's by the simultaneous application of two specific monoclonal antibodies (OKT9 and B3/25) to tissue chopper sections. In the four specimens without iron overload, hepatocytes, but not sinusoidal lining cells, stained positively and immunoreactivity was mainly localized in the cytoplasm. Positively stained cisternae of the endoplasmic reticulum indicated synthesis of the TfR. The presence of TfR's on segments and coated invaginations of the sinusoidal membrane and in small, but otherwise unidentified vesicles in the cytoplasm is compatible with endo-/exocytotic transport and recycling of TfR's as demonstrated by biochemical studies. Occasional positively stained material in canalicular lumina together with positively stained canalicular microvilli and pericanalicular vesicles suggest that transcellular transport may be an additional pathway for TfR's. In three biopsies showing severe iron overload due to HC, TfR immunoreactivity was completely absent. The remaining specimen showing HC, exhibited relatively mild iron overload and showed only a few positively stained hepatocytes. This supports the previously reported disappearance of hepatic TfR expression in HC when iron overload is severe.