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We sought to assess the reliability and validity of the PedsQL™ 4.0 SF15, a shortened version of the 23-item PedsQL™ 4.0 Generic Core Scales, which is a pediatric health-related quality of life (HRQoL) instrument, and the PedsQL™ 3.0 SF22 Asthma Module, a short-form of the PedsQL™ 3.0 Asthma Module.The PedsQL™ 4.0 SF15 and the PedsQL™ 3.0 SF22 Asthma Module were administered by telephone to 125 adolescents (aged 12–18) and 338 parents of children with asthma (aged 2–11). Healthy (n = 451) and chronically ill (n = 422) children, matched by age, respondent status, and ethnicity to the asthma sample, provided data for selected validity tests.The Total Score from the PedsQL™ 4.0 SF15 and the Asthma Symptoms scale and Treatment Problems scale from the PedsQL™ 3.0 SF22 Asthma Module were sufficiently reliable for group comparisons (alpha ≥ 0.70 across all age groups) in the asthma sample. The PedsQL™ 4.0 SF15 and the PedsQL™ 3.0 SF22 Asthma Module were able to distinguish between children of different clinical status and correlated as expected with measures of productivity and family functioning in the asthma sample. The psychometric properties of the PedsQL™ 4.0 SF15 were generally comparable to those of the original instrument.The Total Score of the PedsQL™ 4.0 SF15 and the Asthma Symptoms scale of the PedsQL™ 3.0 SF22 Asthma Module demonstrated the best reliability and validity and should be suitable for group-level comparisons of generic and asthma-specific HRQoL in clinical research studies of children with asthma.