Thalassemia clearly affects the patient's quality of life because of the condition itself and the effects of treatment. Knowledge of the factors associated with health-related quality of life (HRQOL) among patients with thalassemia is essential in developing more suitable clinical, counseling, and social support programs to improve treatment outcomes of these patients. This observational study included 70 patients with thalassemia major attending Hematology Clinic in New Children Hospital, Cairo University, aged 3-18 years, 32 females and 37 males. They were all on iron chelation therapy for 1 or more year, 25 on injectable chelation and 45 on oral chelation therapy. Compliance was significantly higher with oral treatment (P = 0.01). QOL was assessed by the use of the WHOQOL BREF instrument. The highest scores were for the social domain (mean=77.33) while the lowest were for the environmental domain (mean=62.21). Clinical jaundice, mongoloid features and HCV infection significantly affected scores of different domains. The lower the ferritin level the higher the score achieved in different domains. QOL was significantly higher in patients on oral chelation therapy when compared to those on injectable chelation (P=0.013). This study concludes that compliance with iron chelation therapy is closely related to route of administration. Thalassemic children and adolescents have low quality of life scores especially in the psychological domain, and these findings would emphasize the need for psychiatric and rehabilitation programs with aim of increasing motivation and quality of life.