Hepatitis C virus [HCV] infection is the most common transfusion transmitted disease in poly-transfused patients worldwide. In this study we aimed to evaluate the effects of pegylated interferon alfa-2a [PEG-IFN A-2a] in reducing serum ALT and eradicating serum hepatitis C virus [HCV] RNA in HCV infected polytransfused thalassemic patients. A cohort of 51 HCV-RNA positive thalassemic patients were enrolled to our study and received 180 u, g PEG-IFN A-2a once-weekly for 48 weeks. The primary end point was sustained virological response [SVR]. The secondary outcome was normalization of ALT. Patient safety was assured by monthly, and if needed, weekly laboratory assessment and visits. Of 52 patients, 42 participants completed the treatment schedule. A sustained virological response [SVR] was attained in 22/51 [43%] cases. Among non-responders or relapsers to previous HCV antiviral therapy, 9/27 [33%] attained an SVR. Five patients died during treatment and 3 subjects discontinued the therapy because of adverse effects. Adverse events were generally mild, and laboratory abnormalities were rare. A course of 48-week PEG-IFN A-2a monotherapy is effective in eradicating HCV-RNA during treatment. But about one third of thalassemic patients would relapse within 6 months of treatment schedule completion, in whom combination therapy is needed