Background. Interferon(IFN) is expected to prevent the progression of hepatiti s C virus infection to cirrhosis and the development of hepatocellular carcinoma (HCC), but there have been several reports of the development of HCC after a su stained response to IFN. Our aim was to elucidate the incidence and clinical fea tures of, and risk factors for, HCC in sustained responders to IFN, taken for th e treatment of chronic hepatitis C. Methods. We designed a retrospective cohort study conducted at 16 major Hospitals. The subjects were a total of 1056 patient s showing sustained responses, 29 of whom developed HCC. Results. The incidence of HCC per 100 person-years was 0.56 (95%confidence interval, 0.35-0.76) in s ustained responders.By the Cox proportional hazard model, we found that older ag e, higher serum aspartate aminotransferase level,and lower platelet count before IFN therapy were independent risk factors associated with the development of HC C. A risk index of HCC development, based on the coefficients of these risk fact ors, was used to classify patients into three groups, with low, intermediate, and high risk. The inciden ce rates of HCC for these three groups were 0.11, 0.44, and 1.98 per 100 person -years, respectively. The median period to the development of HCC was 4.6 years (range, 1.4-9.0 years), and there were no other specific clinical features of the HCC that developed in these patients. Conclusions. This study suggests that the risk of development of HCC is not completely eliminated in sustained respond ers to IFN. These findings may be useful in determining a follow-up strategy af ter a sustained response to IFN. Background. Interferon (IFN) is expected to prevent the progression of hepatiti s C virus infection to cirrhosis and the development of hepatocellular carcinoma (HCC), but there have been several reports of the development of HCC after a su stained response to IFN. aim was to elucidate the incidence and clinical features of, and risk factors for, HCC in sustained responders to IFN, taken for th e treatment of chronic hepatitis C. Methods. We designed a retrospective cohort study conducted at 16 major Hospitals. The subjects The incidence of HCC per 100 person-years was 0.56 (95% confidence interval, 0.35-0.76) in s ustained responders. By the Cox proportional hazard model, we found that older ag e, higher serum aspartate aminotransferase level, and lower platelet count before IFN therapy were independent risk factors associated with the development of HC C. A risk index of HCC development, b ased on the coefficients of these risk fact ors, was used to classify patients into three groups, with low, intermediate, and high risk. The inciden ce rates of HCC for these three groups were 0.11, 0.44, and 1.98 per 100 person-years , respectively. The median period to the development of HCC was 4.6 years (range, 1.4-9.0 years), and there were no other specific clinical features of the HCC that developed in these patients. Conclusions. This study suggests that the risk of development of HCC is not completely eliminated in sustained respond ers to IFN. These findings may be useful in determining a follow-up strategy af ter a sustained response to IFN.