This study was conducted to clarify the incidence of hepatocellular carcinoma (HCC) and the factors contributing to its occurrence by following chronic hepatitis C patients who received pegylated interferon (PEG-IFN) α-2b plus ribavirin (RBV) combination therapy. Patients who received PEG-IFN α-2b and RBV combination therapy with no history of HCC or HCC within 3 months after the start of treatment were observed for the onset of HCC at 67 centers. Sustained virological response (SVR) was observed in 999 (53.5%) of 1865 patients eligible for analysis. During the observation period (median duration: 4 years and 3 months), HCC developed in 59 patients (3.1%). A significant difference was observed in the 5-year cumulative incidence of HCC between SVR and non-SVR patients (1.1% vs. 7.1%). Factors contributing to HCC selected in multivariate analysis were therapeutic efficacy, sex, age, alanine aminotransferase (ALT) level at 24 weeks after the end of treatment, and platelet count. Non-SVR patients with ALT improvement after the end of treatment had a significantly lower 5-year cumulative incidence of HCC than those without (3.4% vs. 11.0%). HCC developed in 10 patients who achieved SVR, and multivariate analysis indicated that ALT level at 24 weeks after the end of treatment was the only significant factor contributing to HCC. Several known risk factors for HCC contributed to HCC in patients who received PEG-IFN α-2b and RBV combination therapy, and ALT abnormality after the end of treatment contributes to the onset of HCC in both non-SVR and SVR patients.