BACKGROUND: Previous exposure to hepatitis B virus (HBV) and occult HBV infection may have an important role in the development of hepatocellular carcinoma (HCC) in patients with chronic liver disease related to hepatitis C virus (HCV). OBJECTIVE: To prospectively study the association between antibody to hepatitis B core antigen (anti-HBc) and clinical outcomes in patients with HCV-related chronic liver disease. DESIGN: Prospective observational study. SETTING: Kyoto University Hospital and 14 regional core hospitals in Japan. PARTICIPANTS: 872 patients with chronic HCV infection (597 with chronic hepatitis and 275 with cirrhosis). MEASUREMENTS: Incidence of HCC on follow-up (from 1995 to 2005). RESULTS: Only 846 of the 872 enrolled patients were followed. Hepatocellular carcinoma occurred in 237 of 846 patients (28.0%) during follow-up. Among patients with cirrhosis, HCC was diagnosed in 85 of 141 patients (60.3%) with anti-HBc and 58 of 129 patients (45.0%) without HBV-related serologic markers. Of 224 patients with chronic hepatitis who had interferon monotherapy, 92 (41.1%) had sustained or transient disappearance of HCV RNA. None of the anti-HBc-negative patients who had a virologic response to interferon therapy developed HCC, whereas cancer was diagnosed in 4 of 37 anti-HBc-positive patients (10.8%) with a virologic response to interferon. On multivariate analysis using a Cox proportional hazards model, anti-HBc-positive results on serologic testing was an independent risk factor in patients with cirrhosis (incidence rate ratio, 1.58 [95% CI, 1.12 to 2.22]). LIMITATIONS: The study included only 1 assessment of smoking and alcohol consumption at study entry and did not precisely determine the duration of smoking or alcohol use. CONCLUSIONS: Anti-HBc-positive results on serologic testing are a marker of high risk for HCC among patients with HCV-related cirrhosis. Interferon therapy might be less effective in preventing HCC among patients with chronic hepatitis C who are anti-HBc-positive than in those with chronic hepatitis C who are anti-HBc-negative.