OBJECTIVE The purpose of this study was to assess health-related quality of life (QoL) in children with Duchenne muscular dystrophy (DMD), including development and field-testing of a DMD-specific module integrated with the core Pediatric Quality of Life Inventory (PedsQL). METHODS The PedsQL 4.0 Generic Core and DMD Module Scales were completed by 203 families, including 200 parents and 117 boys with DMD. Scores on the PedsQL Core Scales were compared with those of matched healthy children. Relationships between PedsQL scores and patient characteristics were examined. RESULTS By both parent report and child self-report, mean PedsQL scores for boys with DMD were significantly lower than those for healthy children for physical and psychosocial QoL (P < .0001), with significantly impaired psychosocial QoL scores self-reported by 57%. Psychosocial QoL, by self-report only, tended to be higher in the older boys (13-18 years) than in younger boys (8-12 years; P = .05) and was not significantly associated with use of mobility aids. Although parents reported higher Daily Activities scores in boys receiving steroids (P = .01), boys receiving steroids reported no difference in Daily Activities but significantly less worry (P = .004). Parent-child concordance was generally in the fair to poor range. Internal consistency reliability coefficients for PedsQL DMD module scales ranged from 0.66 to 0.86. CONCLUSIONS Overall, boys with DMD reported significantly lower QoL than their healthy peers. Despite decreased physical functioning, older boys seem to perceive better psychosocial QoL than perceived by their parents and by younger boys, unrelated to their need for mobility aids.