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Beta-thalassemia major and its complications have a significant psychological impact, causing emotional burden, hopelessness, and difficulty with social integration.This study was an observational analytical case–control study that included 30 adolescents with a diagnosis of thalassemia, ‘Cases’, and another group of 30 adolescents from the gastrointestinal outpatient clinic, ‘Controls’. All participants were subjected to a semistructured interview, the Patient Health Questionnaire, the Hospital Anxiety Depression Scale, the Middlesex Hospital Questionnaire, and the McGill Quality of Life Questionnaire.Thalassemic adolescents showed statistically significant higher depressive symptoms (P<0.001) and higher anxiety symptoms (P<0.001) compared with adolescents from the gastrointestinal outpatient clinic. There was a highly significant difference in the results of the Middlesex Hospital Questionnaire (P<0.001). Thalassemic adolescents showed significantly higher levels of anxiety, phobia, obsession, somatization, depression, and hysteria. Thalassemic adolescents showed significantly lower levels in different aspects of quality of life, total, general, physical, and emotional, with regard to the McGill Quality of Life Questionnaire (P<0.001).Depressive and anxiety symptoms were more prevalent among adolescents with thalassemia. In addition, in the same group, there was a higher degree of free floating anxiety, phobic anxiety, obsessive symptoms, somatic symptoms, depressive symptoms, and hysteria. Quality of life was highly affected among adolescents with thalassemia.