Maxillary setback of patients with protruded maxilla is a complex procedure. This complexity is aggravated when combined with thalassemia. The Aim of this case report was to treat a beta-thalassemia major girl with severe maxillary protrusion. A 16 year-old beta-thalassemia major girl presented with excessive maxilla, incompetent lips and an everted upper lip was referred for treatment. She had her spleen removed at the age of 9 and her blood transfusion was stopped 3 month before referral. After leveling and aligning with 018 standard edgewise system the patient was sent for Lefort 1 osteotomy. Segmental osteotomy was denied due to excessive bleeding in the procedure. The results showed that the thalassemic patient was effectively treated with presurgical orthodontics, Lefort 1 osteotomy followed by post surgical orthodontics. Very satisfactory esthetic results were obtained in the patient after 4.5 years of active treatment.