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Persistence with Hepatitis C therapy has been identified as a key variable for predicting treatment success. The primary purpose of this study was to assess the persistence with therapy for patients undergoing hepatitis C treatment in the VA healthcare system with two forms of combination therapies: peginterferon alfa-2a with Ribavirin (peg-IFN alpha-2a/Rib) and peginterferon alpha-2b with Ribavirin (peg-IFN alpha-2b/Rib).A retrospective cohort study design was used to analyse persistence in VA patients undergoing hepatitis C therapy during FY 2003–2004 using a large national VA data set. Stringent inclusion and exclusion criteria along with various defining variables were used to identify the inception cohort. Persistence rates were calculated for each of the two treatment groups at 3, 6, 9 and 11 months using the Kaplan–Meier method. Likelihood ratio test of equality between the two treatment groups was performed to detect any differences in persistence rates.A total of 5816 hepatitis C patients formed the inception cohort. Persistence rates for the overall duration showed significantly higher rates for patients on peg-IFN alpha-2a/Rib than peg-IFN alpha-2b/Rib. Cox regression analysis also showed favourable hazard ratio of persistence (0·88) for peg-IFN alpha-2a/Rib over peg-IFN alpha-2b/Rib.Peg alfa-2A/Rib showed slightly higher persistence rates for the overall duration of treatment as compared to Peg alfa-2B/Rib. However the differences, even though statistically significant, are small and not likely to translate into any substantial clinical advantage. Further research involving other approaches is required to confirm these findings.