INTRODUCTION: The etiologic and prognostic factors for non-B, non-C hepatocellular carcinoma (HCC), which is defined by its seronegativity for both hepatitis B surface antigen and hepatitis C virus (HCV) antibody, remain unclear. METHODS: Nonneoplastic liver tissue from 46 patients with non-B, non-C HCC were examined for hepatitis B virus (HBV) DNA and HCV RNA using in situ hybridization. Recurrence-free survival rates were compared between patients showing high or low HBV DNA expression. Other potential prognostic factors were examined as well. RESULTS: HBV DNA was detected in nonneoplastic liver specimens from 35 patents (76.1%), whereas HCV RNA was not detected in any case. In patents with high HBV DNA group expression, recurrence-free survival rates at 1 and 5 years after onset were 68.8% and 13.8%, respectively; those with low expression had higher rates of 89.2% and 59.2%, respectively. Multivariate analysis identified high tumor stage (P=0.042) and high HBV DNA expression (p=0.014) as independent negative prognostic factors. CONCLUSIONS: In many patients with non-B, non-C HCC, HBV DNA in the liver appears to be involved in the carcinogenesis, with intense HBV DNA expression predicting poor outcome for patients with these cancers.