Thalassemia is a common health problem in Mediterranean region including Egypt. Repeated regular blood transfusion with chelation therapy represented the gold standard treatment. However, associated psychiatric disorders could play a role in the pathogenesis and response to treatment. The aim of the work: To assess depression, anxiety and quality of life among adolescents with thalassemia. Methodology: This cohort study included 150 thalassemic adolescents and 150 healthy age and sex matched controls. Each patient was submitted to full history taking, detailed clinical examination and laboratory workup. Then, psychiatric disorders were assessed by Hamilton depression rating scale (HAM-D), Hamilton Anxiety Rating Scale (HAM-A) and McGill quality of life questionnaires. Results: The age ranged between 13 and 18 years, with no significant difference between the study and control groups. Males represented 48.0% and 43.3% of the study and control groups respectively, p >0.05). The majority of patients in thalassemia group diagnosed at their first year (43.3%). Patients in the thalassemia group had significantly lower weight and height. However, consanguinity was significantly higher among the study than the control group (40.7% vs 21.3%). RBCs indices and count were significantly lower, while hemoglobin F was significantly higher in the thalassemia than the control group. The mean HAM-D and HAM-A score were significantly higher in the study than the control group (15.12±3.0, 17.42±5.63 vs 10.94±3.07 and 12.29±5.25, respectively), while McGill QoL score significantly reduced in the study than the control group (5.44±1.11 vs 6.56±0.89, p < 0.001). HAM-D and HAM-A score inversely correlated with quality of life score. And only HAM-A inversely correlated with hemoglobin F in the study group. Conclusion: Transfusion dependent-thalassemia is associated with increased psychiatric (mainly anxiety and depression) and lower quality of life. Interventional programs are recommended for future plans of treatment