OBJECTIVES: To estimate long-term cost-effectiveness of treatment of chronic hepatitis C (CHC) patients with peginterferon alfa-2a (180 mcg/week) versus peginterferon alfa-2b (1.5 mcg/kg/week) both in combination with ribavirin (800-1400 mg/day) from the Spanish National Healthcare System perspective. METHODS: A meta-analysis of head-to-head randomized trials of peginterferon alfa-2a and peginterferon alfa-2b both plus ribavirin, evaluating sustained virological response (SVR) has been recently published. It showed RR= 1.11 (95%CI 1.04-1.19) for all genotypes, RR= 1.21 (95%CI 1.03-1.42) for G-1/4, and RR= 1.11 (95%CI 1.02-1.22) for G-2/3. A Markov model with 7 health states was developed to simulate the disease progression of adult patients with CHC for a lifetime horizon. Efficacy, in terms of SVR, was calculated from the meta-analysis, showing a better SVR rate for peginterferon alfa-2a than for peginterferon alfa-2b: the absolute differences were of 6.0%; 7.6%; and 8.7% for all genotypes, G-1/4 and G-2/3 respectively. Transition probabilities and health states utilities were obtained from published literature. Health direct costs of peginterferon + ribavirin (48 weeks for G-1/4 and 24 weeks for G-2/3) and of disease complications were collected from Spanish databases and studies ([€] 2010). The annual discount rate was 3.5% for costs and outcomes. RESULTS: Each patient gained 0.469, 0.600 and 0.685 life years (LY) and 0.155, 0.198 and 0.227 quality-adjusted life years (QALY) with peginterferon alfa-2a in comparison with peginterferon alfa-2b, for all genotypes, G-1/4 and G-2/3 respectively. The savings per patient treated with peginterferon alfa-2a were €705, €672 and €1900, for all genotypes, G-1/4 and G-2/3, respectively. Peginterferon alfa-2a was the dominant treatment strategy (lower costs and higher efficacy than peginterferon alfa-2b treatment). CONCLUSIONS: Treatment of patients with chronic hepatitis C with peginterferon alfa-2a + ribavirin is a cost-effective strategy in comparison with peginterferon alfa-2b + ribavirin for all genotypes, G-1/4 and G-2/3.