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With regular blood transfusions and modern medical management strategies, transfusion-dependent thalassemia (TDT) patients are currently living into adulthood, but they still suffer from the chronicity of the disease and its complications. This study was aimed to assess the health-related quality of life (HRQoL) scores in pediatric TDT patients compared with healthy controls.The PedsQL 4.0 Generic Core Scales were administered to 80 pediatric TDT patients (aged 5 to 18 y, child self-report) and their parents (parent-proxy report), as well as age-matched and sex-matched healthy controls (80 participants and their parents).Patients with TDT and their parents rated lower HRQoL scores in all domains (physical, emotional, social, and school functioning) compared with the healthy population (P<0.01). The univariate analysis indicated that the total HRQoL score for children’s self-reports was negatively predicted by high ferritin levels and the presence of any complication. The only negative predictor of the total HRQoL score in multivariate analyses was a high ferritin level (>1800 ng/dL).This study showed that thalassemia has a negative impact on HRQoL when compared with a healthy population. For a better quality of life, intensive treatment should be applied for complications and high ferritin levels.