OBJECTIVES:  The aim of this study was to assess the health-related quality of life(HRQoL) of thalassemia patients by comparing it with HRQoL of healthy persons and to evaluate the factors associated with HRQoL among thalassemia patients and level of depression of their caregivers METHODS:  This cross-sectional study was conducted in Thalassemia Center, Bahawal Victoria Hospital, Bahawalpur from February 2016 to March 2016 among 150 patients ranging from 2 to 18 years in age. Patient’s HRQoL was measured using PedsQL (Pediatric Quality of Life) 4.0 generic scale and the depression level in their caregivers was assessed using PHQ-9 (Patient Health Questionnaie-9). HRQoL of healthy control group was also measured using same questionnaires. RESULTS:  The mean score of psychosocial functioning was higher in control group (95.51 74.40) as compared to patients (38.5724.29). The school functioning score (26.8426.08) was lowest of psychosocial measures in thalassemia patients, followed by emotional functioning (30.2330.18) and social functioning (60.1029.87) score. The mean physical health score was found to be 49.2023.92 in patients whereas control group showed the mean score of 89.0611.91. Majority (28%) of the caregivers showed severe depression while 20.7% showed moderately severe depression and (18%) showed mild depression. CONCLUSIONS: In conclusion, thalassemia has substantial negative effect on HRQoL of children and their caregivers. Continuous psychological support from health authorities, improvement in policies made by government and school officials and more understanding from society can be helpful in enhancing quality of life of these patients and their caregivers.