To determine if hepatocellular carcinoma can develop in autoimmune hepatitis in the absence of viral infection and to assess its frequency, liver tissue removed at hepatectomy was tested for HBV DNA and HCV RNA in one patient and the frequency of hepatocellular carcinoma was determined in 212 other uniformly followed individuals. The liver tissue from the propositus was uninfected and only one patient (0.5%) in the cohort undergoing routine follow-up developed malignancy during 1,732 patient-years of observation. Only one of 88 patients with cirrhosis (1%) developed hepatocellular carcinoma during 1,002 patient-years of observation after cirrhosis (mean, 123 +/- 9 months) and of the 65 patients with histological cirrhosis for at least five years, only one developed carcinoma during 162 +/- 8 months (incidence, 1 per 965 patient-years). We conclude that hepatocellular carcinoma can develop in autoimmune hepatitis in the absence of viral infection. Its occurrence is rare and only in long-standing cirrhosis.