The objective of this study was to determine the feasibility, reliability, and validity of the Pediatric Quality of Life Inventory generic core scales (PedsQL questionnaire) in children with sickle cell disease. This was a cross-sectional study of children from an urban hospital-based sickle cell disease clinic and an urban primary care clinic. The study participants were children of ages 2 to 18 years who presented to clinic for a routine visit. Health-related quality of life (HRQL) was the main outcome. HRQL of children with sickle cell disease were compared with children without disease to test validity. Missing items were used to determine feasibility and Cronbach's alpha was used to determine reliability. Parents of 178 children (104 with sickle cell disease and 74 without disease) and 118 children (78 with sickle cell disease and 40 without disease) completed HRQL questionnaires. The PedsQL questionnaire was feasible and reliable. The parent proxy and child self-report questionnaire differentiated between children with and without sickle cell disease. The parent proxy-report differentiated well between children with mild and severe sickle cell disease. The questionnaire performed well in children with sickle cell disease and is a feasible, reliable, and valid tool to measure HRQL in children with sickle cell disease.