Few studies have investigated the quality of life of children with thalassemia in the Middle East or Mediterranean region, especially Iraq. Therefore, this study was performed to assess the health-related quality of life (HRQoL) of patients with β-thalassemia major compared with healthy children and adolescents in the same age group and to evaluate the effects of different iron chelators on HRQoL measurements. A case-control study was performed on patients with β-thalassemia major registered at the Center for Hereditary Blood Diseases in Basra from February 2012 through July 2013. The group included children and adolescents aged 2 to 17 years old. HRQoL was assessed using the Pediatric Quality of Life (PedsQL) Generic Core Scale questionnaire, version 4.0, for children 2 to 12 years old and the Short Form-36 health survey questionnaire, version 2 (SF-36v2), for children and adolescents aged 13 to 17 years old. A total of 209 age-matched and sex-matched children and adolescents were included in the control group. The study did not find a significant difference in PedsQL scores among different age groups or different iron chelators, whereas there were significant differences in all of the SF-36v2 domains, with the best quality of life observed in the deferasirox group, followed by the deferoxamine group and the combined therapy group (P<0.05). The use of deferasirox among patients aged 13 to 17 years old was associated with higher SF-36v2 scores than in the other groups (P<0.05). However, for younger patients, the PedsQL scores were not significantly different for different iron chelators. The use of oral deferasirox significantly improved the quality of life of adolescents with β-thalassemia major. However, this effect was less prominent among patients aged 2 to 12 years old.