Sickle cell disease (SCD) is an inherited blood disorder characterized by a chronic hemolytic anemia that can contribute to fatigue and global cognitive impairment in patients. The study objective was to report on the feasibility, reliability, and validity of the PedsQL™ Multidimensional Fatigue Scale in SCD for pediatric patient self-report ages 5-18 years and parent proxy-report for ages 2-18 years. Procedure. This was a cross-sectional multi-site study whereby 240 pediatric patients with SCD and 303 parents completed the 18-item PedsQL™ Multidimensional Fatigue Scale. Participants also completed the PedsQL™ 4.0 Generic Core Scales. Results. The PedsQL™ Multidimensional Fatigue Scale evidenced excellent feasibility, excellent reliability for the Total Scale Scores (patient self-report α=0.90; parent proxy-report α=0.95), and acceptable reliability for the three individual scales (patient self-report α0.77- 0.84; parent proxy-report α=0.90-0.97). Intercorrelations of the PedsQL™ Multidimensional Fatigue Scale with the PedsQL™ Generic Core Scales were predominantly in the large (≥0.50) range, supporting construct validity. PedsQL™ Multidimensional Fatigue Scale Scores were significantly worse with large effects sizes (≥0.80) for patients with SCD than for a comparison sample of healthy children, supporting known-groups discriminant validity. Confirmatory factor analysis demonstrated an acceptable to excellent model fit in SCD. Conclusions. The PedsQL™ Multidimensional Fatigue Scale demonstrated acceptable to excellent measurement properties in SCD. The results demonstrate the relative severity of fatigue symptoms in pediatric patients with SCD, indicating the potential clinical utility of multidimensional assessment of fatigue in patients with SCD in clinical research and practice. © 2013 Wiley Periodicals, Inc.