OBJECTIVES: To present pharmacoeconomic evidence supporting the relative cost-effectiveness of two pegylated interferon therapies, compared with the standard interferon and ribavirin therapy, for hepatitis C treatment. METHODS: Evidence-based decision analysis based on genotypes, treatment dose and duration, comparing the pharmacoeconomic benefits of PEGASYS + COPEGUS (peginterferon alfa-2a + ribavirin) versus REBETRON (interferon alfa-2b + ribavirin) and PEG-Intron + REBETOL (peginterferon alfa-2a + ribavirin) versus REBETRON. Cost effectiveness is calculated in terms of the cost per sustained virological response (SVR); timeframe includes the course of therapy and treatment-free follow-up of 24-weeks. The model adopts a managed care perspective and includes only direct costs. Each therapy efficacy rates, total costs, costs associated with diagnosis, medical treatment, drug acquisition and adverse events are calculated for base-case scenario and sensitivity analyses. RESULTS: Drugs accounted for the largest portion of total costs, followed by adverse events, diagnostic procedures and medical treatment. The total costs associated with PEG-Intron+REBETOL ($29,510) compared with REBETRON ($25,864) imply an incremental cost-effectiveness ratio (ICER) for PEG-Intron+REBETOL versus REBETRON of $60,767. PEGASYS + COPEGUS provide an increased probability of treatment success at a lower cost than REBETRON. Compared with REBETRON, the combination of PEGASYS + COPEGUS is deemed a dominant strategy. The results of the sensitivity analysis indicate that the results of the model are robust to changes in the base case parameters and the ICERs for PEGASYS + COPEGUS versus REBETRON are consistently lower than the ICERs of PEG-Intron + REBETOL versus REBETRON. CONCLUSIONS: The pegylated interferons provide a cost-effective, if not cost-savings alternative to standard interferon + ribavirin. In addition to the direct cost savings, PEGASYS + COPEGUS dominate REBETRON with better efficacy at a lower cost. The model presented in this study is a critical tool to aid decision-making for therapies that have the potential to improve public health in large populations.