OBJECTIVE: To examine the associations between demographic and diabetes management variables and the health-related quality of life (HRQOL) of youths with type 1 or type 2 diabetes mellitus (DM). DESIGN: Cross-sectional study. SETTINGS: Selected populations in Ohio, Washington, South Carolina, Colorado, Hawaii, and California; health service beneficiaries in 3 American Indian populations; and participants in the Pima Indian Study in Arizona. PARTICIPANTS: Two thousand four hundred forty-five participants aged 8 to 22 years in the SEARCH for Diabetes in Youth Study. MAIN OUTCOME MEASURE: Pediatric Quality of Life Inventory scores. RESULTS: Among youths with type 2 DM, HRQOL was lower compared with those with type 1. Among those with type 1 DM, worse HRQOL was associated with a primary insurance source of Medicaid or another government-funded insurance, use of insulin injections vs an insulin pump, a hemoglobin A(1c) value of at least 9%, and more comorbidities and diabetes complications. There was a significant age x sex interaction, such that, in older groups, HRQOL was lower for girls but higher for boys. For youths with type 2 DM, injecting insulin at least 3 times a day compared with using an oral or no diabetes medication was associated with better HRQOL, and having 2 or more emergency department visits in the past 6 months was associated with worse HRQOL. CONCLUSIONS: Youths with types 1 and 2 DM reported HRQOL differences by type of treatment and complications. The significant age x sex interaction suggests that interventions to improve HRQOL should consider gender differences in diabetes adjustment and management in different age groups.