Background: Thalassemia is the most prevalent cause of chronic hemolytic anemia and associated with high rates of morbidity and mortality. Its management is demanding, timely and multidisciplinary creating a strain on the patients, their families, and society. Aim of the work: To study the effect of the corona virus disease of 2019 (COVID-19) pandemic lockdown on the health-related quality of life (HRQoL) of the children with transfusion- dependent thalassemia. Subjects and Methods: The HRQoL (child self-report) and (parent proxy-report for those children) questionnaires of the Pediatric Quality of Life Inventory (PedsQL) Measurement Model were used to study the same group of 131 children with transfusion-dependent-thalassemia before and during the-COVID-19 era lockdown and compared them to 200 matched children with their parents as a control group. Results: 67 (51.1%) males and 64 (48.9%) females, transfusion-dependent thalassemia patients were included in our study. The mean age was 8.28 ± SD3.81 (range 5-18) and 8.94 ±SD 3.78 years at initial assessment and during the lockdown respectively (p=0.0001). in the pre-COVID- 19 the score of patients in all the aspects of PedsQL questionnaire was 60.4±22.8 while that of the control group was 97.3±3 (p