Transfusion-dependent thalassemia (TDT) and its treatment affect the physical, emotional, and social functioning, impairing the quality of life (QoL). There are few studies on QoL of adolescent with TDT. Its effect on their siblings’ QoL has not been studied so far. In this cross-sectional study, 40 adolescents with TDT, 28 siblings, and 40 controls were studied to assess the QoL of adolescents thalassemics, and their siblings using the shorter version of World Health Organization Quality of Life instrument, the WHOQOL-BREF. Thalassemics had poor perception of their general health and scored significantly lower in all the subscales compared with the controls. Lowest mean subscale scores were for physical (57.7 vs. 72.4, P<0.001), and psychological domains (56.7 vs. 72.3, P<0.001). Their siblings also scored significantly less in environment domain. Prevalence of school dropout, short stature, and delayed puberty were significantly higher in thalassemics. Pretransfusion hemoglobin, age at onset of anemia, and chronological age were found to be significant predictors of total summary scores. This study showed that the concept of QoL is a cumulative reflection of individual and disease variables and highlights the negative impact of thalassemia on the patients’ QoL and some aspects of their siblings’ lives also.