To identify specific environmental, viral, and genetic risk factors for hepatocellular carcinoma (HCC) and the interaction of such factors, we are conducting a prospective study in a high-incidence area of China. Questionnaires were completed and biosamples collected by 60,984 men ages 30-64 years, at study entry. Within 2.5 years, 183 deaths from HCC had occurred. Each HCC case was matched with 5 controls and compared for items on the questionnaire. In addition to chronic hepatitis B virus (HBV) infection, the significant risk factors were: occupation (peasant), corn consumption (in the 1970s), family history of HCC, and history of an episode of acute hepatitis as an adult. HBV, consumption of aflatoxins, a genetic factor, and possibly a second hepatitis virus infection contribute to the risk of HCC.