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Low quality of life (QOL) is a feature that has been overlooked in thalassemia major (TM) patients. Our aim was to assess QOL in school-aged TM patients in Zabol city and surrounding rural areas in southeast of Iran. The study was performed in 2014. QOL was evaluated using Pediatric Quality of Life Inventory 4 (PedsQL4) questionnaire addressing physical, emotional, social, and educational, along with psychological health in 80 TM patients. Also, 80 age-matched and sex-matched subjects without any chronic illness served as control group. Mean age of the patients was 11.7±4.1 years old. Total QOL scores was 51.4±13.3 in the patients. In comparison, mean value of total QOL score in controls was 91.1±3.3 (P<0.0001). Poor and moderate QOL were observed in 44.7% and 48.7% of the patients, respectively. Mean functioning scores for physical, emotional, social, educational, and psychological dimensions in the patients were 56.2±119, 69.6.4±23.3, 27.1±22.1, 52.3±18.1, and 48.9±11.8, respectively. The lowest level of QOL was related to the social field (81.3% with less than average score), while the highest QOL was related to the emotional aspect (58.8% with good QOL; >75 scores). Overall, female sex, poor compliance with chelation therapy, and residency in urban areas were significantly associated with poor QOL. In conclusion, providing a psychiatric health package seems to be essential for improving QOL in TM patients, especially in social field.