Background & Aims: Therapeutic options for patients failing hepatitis C retreatment are limited. EPIC3 included a prospective trial assessing long-term peginterferon alfa-2b (PegIFNα-2b) maintenance therapy in patients with METAVIR fibrosis scores (MFS) of F2 or F3 who previously failed hepatitis C retreatment. Methods: Patients with F2/F3 MFS who failed retreatment were randomized to PegIFNα-2b (0.5μg/kg/week, n=270) or observation (n=270) for 36months. Blinded liver biopsies obtained before retreatment and after maintenance therapy were evaluated using MFS and activity scores, and confirmatory testing was performed using FibroTest and ActiTest. Results: In total, 348 patients had paired biopsies: 192 patients had missing post-treatment biopsies and were considered as having no change in fibrosis/activity scores. In total, 16% of patients receiving PegIFNα-2b and 11% of observation patients had improvement in MFS (p =0.32). More PegIFNα-2b than observation patients had improvement in activity score (20% vs. 9%; p <0.001). Among patients treated for >2.5years, improvement in MFS or activity score was more common with PegIFNα-2b than observation (21% vs. 14%, p =0.08 and 26% vs. 10%, p <0.001). FibroTest and ActiTest evaluations indicated significant benefit associated with PegIFNα-2b in terms of reduced fibrosis progression and improved activity score. The safety profile of PegIFNα-2b was similar to previous studies. Conclusions: PegIFNα-2b did not significantly improve MFS estimated by biopsy compared with observation; however, activity scores were significantly improved and MFS trended toward increased improvement with treatment durations >2.5years. Both FibroTest and ActiTest were significantly improved during maintenance therapy. [ABSTRACT FROM AUTHOR]