Background and Objectives: Patients with beta-Thalassemia major (b-TM) in dealing with the serious complications of the disease experience many physical and psychological problems that affect their quality of life (QOL). The aim of this study was to determine QOL, depression, anxiety and stress in b-TM patients over 18 years of age.Materials and Methods: The participants of this cross-sectional study were142 β-TM patients (77 female, 65 male) having referred to the Thalassemia Clinic of Shafa Hospital in 2014; they were entered into the study by the census method. Data collection instrument consisted of three parts including demographic questions, the SF-36 questionnaire and the DAS-21 scale. The data were analyzed using descriptive statistics, independent sample t- test, one way ANOVA and correlation in SPSS software v.19.Results: The participants obtained a mean score of 63.53±18.12 for QOL, 6.64±5.07 for depression, 5.03±3.95 for anxiety and 7.68±4.98 for stress. The significant inverse correlations were found between QOL and that of depression (p<0.001, r=-0.58), anxiety (p<0.001, r=-0.52), and stress scores (p<0.001, r=-0.45). The mean scores of QOL were higher in the patients with college degrees, being employed, being married, under regular chelation therapy without presence of comorbidities. The mean scores of depression, anxiety, and stress werehigher in patients with education≤high school diploma, being poorly complied with iron-chelating therapy in presence of comorbidities.Conclusions: The study showed that b-TM patients experienced a considerable decrease in their QoL. A majority of the patients also suffered from mild to severe depression, anxiety and stress. Obviously, the health improvement, and social and economic as well as psychological support may raise their QOL.