For Phase II and III clinical trials in children with Spinal Muscular Atrophy (SMA), reliable and valid outcome measures are necessary. Since 2000, the American Spinal Muscular Atrophy Randomized Trials (AmSMART) group has established reliability and validity for measures of strength, lung function, and motor function in the population from age 2 years to 18 years. The PedsQL (Pediatric Quality of Life Inventory) Measurement Model was designed to integrate the relative merits of generic and disease-specific approaches, with disease-specific modules. The PedsQL 3.0 Neuromuscular Module was designed to measure HRQOL dimensions specific to children ages 2-18 years with neuromuscular disorders, including SMA. One hundred seventy-six children with SMA and their parents completed the PedsQL 4.0 Generic Core Scales and PedsQL 3.0 Neuromuscular Module. The PedsQL demonstrated feasibility, reliability, and validity in the SMA population. Consistent with the conceptualization of disease-specific symptoms as causal indicators of generic HRQOL, the majority of intercorrelations among the Neuromuscular Module Scales and the Generic Core Scales were in the medium to large range, supporting construct validity. For the purposes of a clinical trial, the PedsQL Neuromuscular Module and Generic Core Scales provide an integrated measurement model with the advantages of both generic and condition-specific instruments.