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Evaluate the validity of the Pediatric Quality of Life Inventory (PedsQL) for sickle cell disease (SCD).Sixty-eight parent–child dyads (children 5–18 years) completed the PedsQL. Medical record review assessed history of specific morbidities.Internal consistency of the scales varied. The strongest reliability was for parent proxy-report for specific domains or for global functioning scores with either informant. Modest internal consistency was found for specific domains with child informants, particularly for younger children. Moderate convergent validity was found between informants. History of neurologic problems or major pain episodes indicated criterion validity for specific scales.The PedsQL appears to validly assess quality of life in youth with SCD. Domain-specific measurement of quality of life was limited by (a) low reliability for youth-report and (b) lack of discriminant validity. Choice of informant may be important when evaluating quality of life effects from pain or neurologic problems in SCD.