BACKGROUND: Thalassemia is an inherited blood disease. It is a serious public health problem throughout the Mediterranean region, the Middle East and the Indian subcontinent, as well as in Southeast Asia. OBJECTIVES: Thalassemia is an inherited blood disease. It is a serious public health problem. In this study we assessed psychological aspects in Iranian children and adolescents with thalassemia major. PATIENTS AND METHODS: In this case-control study sixty healthy subjects aged 7-18 years and Sixty Patients with confirmed diagnosis of major thalassemia were enrolled. After obtaining informed consent from parents of all participating thalassemia patients and healthycontrols, we assessed psychological aspects and quality of life by Pediatric Quality of LifeTM (PedsQL), Strengths and Difficulties Questionnaires (SDQ), State and Trait Anxiety, Children’s Depression Inventory (CDI). RESULTS: The results of this study indicate that there are significant changes in depression, anxiety, QOL and behavioral screening between children with thalassemia major compared with healthy subjects by means of both parents and children reports. According to the results, children with thalassemia major have more psychological problems than healthy ones. Patients with thalassemia have a lower QOL than their peers (P = 0.001), the rate of depression is higher in this group (P = 0.015), Also behavioral problems in these children are more than healthy subjects (P = 0.009). CONCLUSIONS: We recommend appropriate treatment and counseling procedures in addition to specific treatment of thalassemia. According to the results we suggest to establish pediatric psychiatric clinics beside thalassemic clinics to cure psychological aspects of the disease.