Health-related quality of life (HRQOL) of youths with sickle cell disease (SCD) has not been described, despite the psychosocial and physical consequences associated with the disease. We compared the HRQOL of 58 children with SCD to a demographically similar sample of 120 healthy children and examined predictors of HRQOL. Child HRQOL was assessed using the Child Health Questionnaire--Parent Report Form. Review of medical charts of children with SCD provided data on disease-related complications. Results demonstrated that caregivers of children with SCD reported that their children had more limited physical, psychological, and social well-being than healthy children. Older child age, female gender, and more disease-related complications predicted limitations in the physical health of children with SCD. The findings indicated that SCD significantly affects the HRQOL of youths. Certain subgroups of patients (e.g., children with more disease complications) may benefit from interventions specifically designed to improve their physical functioning.