OBJECTIVES To compare the cost-effectiveness of peginterferon alpha 2a or alpha 2b, plus ribavirin, in the treatment of Hepatitis C virus chronic infection, from an institutional perspective, in the Mexican setting. METHODS Using a decision tree, a Hepatitis C virus chronic infection 1-year treatment was modeled. The effectiveness of each treatment against genotypes 1, 2, or 3 was obtained using a previously published meta-analysis; the effectiveness measure was the percentage of patients who obtained a sustained viral response. Epidemiological data were included for genotype population distributions in Mexico. The utilized health care resources were derived from the Hepatitis C National Consensus and records from a reference hospital, whereas costs were obtained from purchasing records from a public institution. Costs were estimated using prices of 2008 and are expressed in US dollars (exchange rate of 11.14 pesos/ 1 US$). RESULTS The cost for drugs accounted for over 80% of total treatment cost. Average costs per patient treated were: $8,422.16 for peginterferon alpha 2b + ribavirin vs. $9452.59 for peginterferon alpha 2a + ribavirin. Effectiveness achieved in obtaining a case with sustained viral response for peginterferon alpha 2b + ribavirin was 12% higher compared to peginterferon alpha 2a + ribavirin. Average cost–effectiveness ratios corresponding to cost per patient with sustained viral response were $14,921.42 for peginterferon alpha 2b + ribavirin: and $21,221.53 for peginterferon alpha 2a + ribavirin. Incremental cost–effectiveness ratios obtained in the model show peginterferon alpha 2b + ribavirin treatment as the most cost–effective or dominant strategy, since using peginterferon alpha 2a + ribavirin has a cost of $8658.28 pesos for an additional patient to present sustained viral response. CONCLUSIONS Ribavirin plus peginterferon alpha 2b combination was the most cost-effective treatment, in the Mexican context, according to the proposed decision tree model.