The risk of hepatocellular carcinoma in autoimmune hepatitis is low, even in patients with long-standing cirrhosis. Because of the increasing recognition of an association of hepatitis C virus (HCV) with autoimmune hepatitis, at least in some geographical areas, and with hepatocellular carcinoma (HCC) (hepatoma), we have examined eight cases (4 male, 4 female) who presented between 1985 and 1993 with hepatoma complicating autoimmune hepatitis. All had steroid-responsive autoimmune hepatitis with serum anti-smooth muscle and anti-nuclear autoantibodies. Median duration of disease was 17.1 years, and all patients had biopsy-proven cirrhosis. One patient had a history of intravenous drug abuse, and four had previously received blood transfusions. Serum samples (stored at -20 degrees C from up to 9 years before diagnosis of hepatoma) were tested for anti-hepatitis C virus antibodies by a second-third-generation assay and for HCV RNA by the polymerase chain reaction method using primers from the 5'noncoding region. Tissue from liver adjacent to tumor areas was subjected to polymerase chain reaction along with tissue from previous liver biopsy specimens (taken up to 19 years before diagnosis of hepatoma) in all patients. Six patients had evidence of HCV infection: four seropositive for HCV RNA (two of whom were also anti-HCV positive) and two seronegative for HCV RNA and anti-HCV but with HCV RNA in liver tissue at presentation with hepatoma. Retrospective testing showed probable acquisition of HCV through blood transfusion in the four transfused patients.(ABSTRACT TRUNCATED AT 250 WORDS)