Introduction: Iron overload remains a critical challenge in transfusion-dependent beta thalassemia major patients, necessitating effective chelation strategies. This study evaluated the comparative efficacy of combination therapy (deferoxamine plus defera-sirox) versus deferasirox monotherapy in patients with severe iron overload. Methods: In this prospective, randomized controlled study, 50 transfusion-dependent beta thalassemia major patients with se- rum ferritin levels between 3,000-5,000 ng/mL were randomized into two groups. Group A (n=25) received combination therapy with subcutaneous deferoxamine (40-50 mg/kg/day, 5 days/week) plus oral deferasirox (20-30 mg/kg/day), while Group B (n=25) received deferasirox monotherapy (30-40 mg/kg/day). Patients were monitored over 12 months with regular assessment of serum ferritin levels, organ iron content, and safety parameters. Results: At 12 months, the combination therapy group demonstrated significantly greater reduction in serum ferritin levels compared to the monotherapy group (44.9% vs 24.9%, p