Detection of proliferating cell nuclear antigen is useful for the study of proliferative activity of neoplastic and non-neoplastic lymphoid, parenchymal, and mesenchymal cells. Allograft rejection is associated with the recruitment of circulating cells and their proliferation in the graft. The intrahepatic expression of proliferating cell nuclear antigen on paraffin-embedded liver biopsy specimens (n = 110 from 32 patients) was examined by an avidin-biotin peroxidase method using a monoclonal antibody to proliferating cell nuclear antigen. The percentage of positive nuclei was determined in hepatocytes, biliary epithelium, and lymphocytes. There were four histologic groups: 1, moderate-to-severe rejection (n = 19); 2, mild rejection (n = 28); 3, nonspecific inflammation (n = 45); and 4, donor livers (n = 18). The percentage of positive nuclei was higher in group 1 compared to group 2 (hepatocytes p = 0.01; biliary epithelium p = 0.0007; lymphocytes p = 0.0001), to group 3 (hepatocytes p = 0.0002; biliary epithelium p = 0.0001; lymphocytes p = 0.0001), and to group 4 (for all three locations p < 0.0001). When group 2 was compared to group 3 the results were significant for biliary epithelium (p = 0.0001) and lymphocytes (p = 0.0001), but not for hepatocytes (p = 0.07). We conclude that proliferating cell nuclear antigen expression, especially in lymphocytes, correlates with the severity of histologic rejection. Proliferating cell nuclear antigen expression may be useful in predicting the progression and response to different antirejection therapies.