OBJECTIVES: The objective of this study was to examine the psychometric properties of the Pediatric Quality of Life Inventory 4.0 Generic Core Scales (PedsQL 4.0 GCS) in Duchenne muscular dystrophy (DMD), a rare, severely debilitating, and ultimately fatal neuromuscular disease. METHODS: Patients with DMD were recruited from 20 centres across nine countries as part of the Cooperative International Neuromuscular Research Group Duchenne Natural History Study (NCT00468832). The psychometric properties of the PedsQL 4.0 GCS were examined using Rasch analysis. RESULTS: In total, 329 patients with DMD (mean age: 9 years, range: 3–18 years; 75% ambulatory) completed the PedsQL 4.0 GCS. The most difficult instrument items, expressing the greatest loss in HRQoL, were those associated with emotional well-being (e.g., being teased by other children, feeling sad, and not making friends), as opposed to somatic disability (e.g., lifting heavy objects, participating in sports, and running). The mean item and person fit residuals were estimated at 0.301 (SD: 1.385) and −0.255 (1.504), respectively. In total, 87% (20 of 23) of items displayed disordered thresholds, and many exhibited non-trivial dependency. The overall item-trait interaction [Formula: see text] value was 178 (115 degrees of freedom, p