The aim of this study was to investigate the efficacy and safety of oral iron chelators, deferiprone in combination with desferrioxamine in comparison with desferrioxamine alone. A total of 70 transfusion-dependent thalassemia major patients were randomly selected to receive one of the following two treatments: deferiprone in combination with desferrioxamine (n=35, desferrioxamine+deferiprone group) or desferrioxamine alone (n=35, desferrioxamine-only group). Changes in serum ferritin, liver enzymes (alanine aminotransferase and aspartate aminotransferase), blood urea nitrogen, and creatinin were evaluated before the treatment and then six and 12 months after the treatment, and any side effect caused by iron chelators was reported during the study. Student's t-test and repeated measures were used to compare different mean values for quantitative data and Chi-square to compare qualitative data. Serum ferritin decreased more significantly in patients on desferrioxamine+deferiprone therapy compared to patients who only received desferrioxamine (P<0.017). Side effects of deferiprone, including neutropenia, severe gastrointestinal upset, and arthropathy occurred in eight, four, and two patients, respectively but none led to discontinuation of the treatment. Beta-thalassemia major patients with iron overload due to transfusion could be successfully treated with a combination of desferrioxamine and deferiprone. This regimen is more effective than desferrioxamine-only therapy in decreasing serum ferritin; therefore, it also could be more effective in reducing iron overload and related complications in beta-thalessemia major patients.