In a community-based prospective study, the authors examined the independent and interactive effects of hepatitis C virus (HCV) infection and cofactors, including hepatitis B virus (HBV) infection and lifestyle habits, on the incidence of hepatocellular carcinoma (HCC) in Taiwan. At baseline recruitment, subjects were evaluated with regard to second-generation HCV antibody (anti-HCV), hepatitis B surface antigen, and serum alanine aminotransferase, as well as cigarette smoking, alcohol drinking, and betel quid chewing habits. A total of 12,008 male residents aged 30-64 years without a history of HCC were included in the study. Between July 1990 and June 2001, 112 incident cases of HCC were identified among the subjects and included in the analysis. Persons with anti-HCV positivity alone had a 20-fold increased risk of developing HCC in comparison with those who were negative for anti-HCV. In statistical assessment of additive interaction, HCV and HBV tended to act independently in the pathogenesis of HCC. The results of this study suggest that HCV plays a significant role in hepatocarcinogenesis in an area endemic for chronic HBV infection.