OBJECTIVES: When comparing combined therapy with peginterferon alpha-2a or alpha-2b and ribavirin to treat chronic hepatitis C (CHC), the results of clinical trials, observational studies, and meta-analyses have been inconsistent. Their effectiveness and tolerability were investigated using the nationwide database of chronic hepatitis patients who received interferon therapy in Japan.  METHODS: The proportion with a sustained virologic response (SVR) and the dropout rate due to adverse events (AEs) were compared between alpha-2a and alpha-2b. All patients also received ribavirin. Multivariate logistic regression was conducted with adjustment for age, sex, platelet counts, ALT, viral load, genotype, and whether the patient was treatment-naïve, which are associated with effectiveness and tolerability.  RESULTS: By December 2011, the database included 7820 patients. CHC patients treated with either alpha-2a (n=1737) or alpha-2b (n=4495) were analyzed. The mean (SD) age was 58.1 (10.4) years, and 3131 (50.2%) were female. In total, 2503 (41.0%) patients had a platelet count <150x103, 2503 (40.5%) had ALT > 60 IU/L, and 5765 (93.2%) had a high viral load. The numbers with genotype 1, 2, and 3 were 4291 (69.2%), 1838 (29.6%), and 76 (1.2%), respectively. Overall, 4434 (71.2%) patients were treatment-naïve. SVR was achieved in 53.5% (95% CI: 51.1-55.9%) with alpha-2a and 61.6% (95% CI: 60.2-63.1%) with alpha-2b (p<0.001). The dropout rate due to any AEs was 10.3% (95%CI: 8.9-11.8%) and 9.3% (95%CI: 8.5-10.2%) for alpha-2a and alpha-2b, respectively (p=0.226). After adjustment for possible confounders, no differences in effectiveness or tolerability were observed between the therapies, and the odds ratio of alpha-2a for SVR was 0.97 (95% CI: 0.86-1.10), and its odds ratio for dropout due to any AEs was 0.96 (95% CI: 0.79-1.17). There was no significant interaction of genotype and therapy.  CONCLUSIONS: Alpha-2a and alpha-2b in combination with ribavirin showed comparable effectiveness and tolerability in clinical settings.