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Objective To determine if caregiver report of the Pediatric Quality of Life Inventory (PedsQL) is responsive to changes in health-related quality of life (HRQL) associated with pain episodes in pediatric sickle cell disease (SCD). Methods 81 caregivers of children ages 2–19 years with SCD completed the PedsQL as part of routine psychosocial screenings at 2 time points, ranging from 6 to 18 months apart. Frequency of SCD-related pain episodes between time points was assessed using medical chart review. Results The frequency of pain episodes between time points was a significant predictor of decreases in physical, psychosocial, and total HRQL, even after controlling for time interval, demographic, and medical variables. Conclusions The caregiver report of the PedsQL appears to be a useful tool for capturing changes in HRQL over time associated with pain episodes in SCD.