Using in situ immunohistochemistry and a specific monoclonal antibody (mcab R1G10), we analyzed the expression of the human interferon-gamma receptor (HuIFN-gamma R) and its topographical distribution in normal liver biopsies and in biopsies with various inflammatory liver diseases. In normal liver tissue, mcab R1G10 reacted weakly with sinusoidal and vascular endothelial cells, while hepatocytes were distinctly negative. In pathological conditions, mcab R1G10 produced membranous, cytoplasmic and/or perinuclear staining of hepatocytes, in a topographical distribution which varied according to the type of liver disease. In acute hepatitis, R1G10-positive hepatocytes were diffusely distributed throughout the liver parenchyma, and showed strong cytoplasmic, as well as membranous and perinuclear reactivity. In chronic persistent hepatitis, weak membranous staining was found on a number of scattered hepatocytes in acinar zone 1, with more pronounced expression on single hepatocytes in acinar zone 3. In chronic active hepatitis and in active cirrhosis, a diffuse weak membranous reactivity throughout the liver parenchyma was accompanied by enhanced R1G10 expression in areas of inflammation in acinar zone 1. With immunoelectronmicroscopy, R1G10 reactivity was found on the peripheral cell membrane and on the microvillous canalicular cell membrane of hepatocytes in a strikingly discontinuous manner. In the cytoplasm, the reaction product was detected on the cisternae of the rough endoplasmic reticulum and on small vesicles which were especially abundant in the perinuclear area. Our results demonstrate the absence of HuIFN-gamma R on hepatocytes in the normal liver, and its de novo expression during inflammatory liver disease. These findings indicate that hepatocytes, by displaying the HuIFN-gamma R, may act as target cells for the immunoregulatory action of IFN-gamma during liver inflammation.