BACKGROUND: Interferon (IFN) regimens for HCV treatment are less effective in HCV/HIV-coinfected patients. There are no effective treatments for patients who fail IFN therapies. We examined the safety and efficacy of peginterferon alfa-2a (peg-IFNalpha-2a) plus ribavirin (RBV) in 41HCV/HIV-coinfected patients non-responsive to prior IFN treatment. METHODS: Patients received peg-IFNalpha-2a (180mg/week) plus RBV (800mg/day) for 24 weeks (n=41). At week 24, patients with non-detectable HCV RNA or > or =2-log decrease from baseline, received peg-IFNalpha-2a (180mg/week) plus RBV (800mg/day) for 24 weeks further. Patients not responding to treatment at week 24 were discontinued. RESULTS: Intent to treat (ITT) sustained viral response (SVR) was 21.9%. Patients who received at least 24 weeks of peg-IFNalpha-2a plus RBV treatment (n=35), SVR rates were 25.7%. SVR was associated with significant improvements in liver histology grade (p=0.02), stage (p=0.02), and fibrosis progression rate (FPR) (p=0.03). Patients that failed to achieve SVR had statistically significant decreases in grade (p=0.09) and FPR (p=0.01). CONCLUSION: peg-IFNalpha-2a plus RBV is effective and safe to achieve SVR in HCV/HIV coinfected patients non-responsive to prior IFN treatment. Patients that achieve SVR have significant improvements in liver histology parameters. In patients that do not achieve SVR there are histological benefits beyond virological response that suggest that peg-IFNalpha-2a+RBV therapy may decrease risk of progression to end stage liver disease.