It has been suggested that in fulminant hepatitis it is the lack of hepatocyte regeneration that in the presence of an ongoing loss of hepatocytes leads to hepatic failure and ultimately determines the grim prognosis of this disease. However, little data are available concerning hepatocyte regeneration in human acute hepatitis. We compared the nuclear expression of proliferating cell nuclear antigen with the incorporation of bromodeoxyuridine in formalinfixed, paraffin-embedded liver tissues of rats at dif- ferent stages of regeneration after two-thirds partial hepatectomy. Immunohistochemical staining for proliferating cell nuclear antigen was performed using the monoclonal antibody 19F4. A good correlation was seen between nuclear labeling for bromodeoxyuridine and proliferating cell nuclear antigen, which indicates that the immunoreactivity for proliferating cell nuclear antigen accurately reflects hepatocyte proliferation. Subsequently, we determined the nuclear expression of proliferating cell nuclear antigen on archival paraffin-embedded samples of the normal human liver ( 8 cases), acute nonfulminant hepatitis (10 cases) and fulminant hepatitis (4 cases). The mean proliferating cell nuclear antigen labeling indices were the following: normal liver = 0.4%; acute nonfulminant hepatitis = 43.0%; and fulminant hepatitis = 45.9%. The indices for proliferating cell nuclear antigen were significantly greater in acute hepatitis than in the normal liver, reflecting the high cell turnover in hepatitis. However, no significant difference was seen between the expression of proliferating cell nuclear antigen in nonfulminant and fulminant acute hepatitis. These data suggest that the net loss of hepatocytes in fulminant hepatitis may not be caused by a lack of hepatocyte regeneration but rather results from overwhelming hepatocyte injury with subsequent cell death. (HEPATOLOGY 1992; 15707-713.)