Background: The aim of this study was to evaluate the effectiveness of monotherapy with interferon alpha- 2b and combination therapy with interferon alpha- 2b plus ribavirin on chronic hepatitis C infection in thalassaemic patients. Methods: In parallel group randomized, double blind, controlled trial, 32 thalassaemic patients with chronic hepatitis C infection completed the study. In a random fashion, one group was treated with three million units of interferon alpha- 2b three times a week plus ribavirin (800- 1200 mg daily). The second group received interferon alpha- 2b alone. Treatment duration was 24- 48 weeks. Primary efficacy variables were HCV RNA after treatment and sustained viral response (SVR) six months after treatment. Results: The mean age of patients was 22 ± 7.4 years; 19 (59.4%) were male and 13 (40.6) were female. At the end of treatment, no statistically significant differences were found between the groups in HCV RNA and AST. The proportion of patients with SVR six months after treatment was significantly greater in the monotherapy group (90.9%) than in the combination therapy group (44.4%; p = 0.049). A significant difference in mean of ALT was also obtained at the end of treatment between monotherapy and combination therapy groups (30.4 ± 19.2 and 60.1 ± 48.9, respectively; p = 0.02). Response rates were not associated with genotype and severity of hepatitis C infection in both groups. Conclusions: These results suggest that monotherapy may be considered as the first- line therapy in patients with thalassemia.