Fifty-five cases representing a spectrum of disease states of the human liver and 10 normal liver controls were examined for the presence of the ras oncogene product p21. Conventional formalin-fixed, paraffin-embedded sections were immunostained by the avidin-biotin complex method with the broadly reactive ras p21 monoclonal antibody (Mab) RAP-5. The specificity of the reactions was confirmed by immunostaining selected samples with Mab Y13-259. In the normal liver, virtually no hepatocytic immunostaining was noted. Variable, often extensive, and convincing immunoreactions were noted in diverse forms of hepatitis, cirrhosis, and allograft rejection; the strongest immunostaining was found in samples of focal nodular hyperplasia. Hepatic adenomas and hepatocellular carcinomas showed unevenly distributed, moderate to weak reactions or no reaction at all; cholangiocarcinomas did not immunostain. In reactive but non-transformed liver cell populations, enhanced p21 ras reactions seemed to correlate with the severity of the injury and the intensity of the proliferative response. The uneven and comparatively weak ras p21 reactions noted in adenomas and carcinomas suggest that this oncogene product may be involved only transitorily in their transformation processes and possibly may not be involved in certain variants thereof.