Background: Children with sickle cell disease (SCD) experience a multiplex of disease-related symptoms and complications, including vaso-occlusive crises (VOCs), episodes characterized by extreme pain., Methods: A cross-sectional observational survey examined the health-related quality of life (HRQoL) and school experiences of children with SCD 2 months-11 years, burden experienced by their caregivers, and associations between these outcomes and VOC frequency. Caregivers (N=167) of children with SCD in the US completed the Infant-Toddler Quality of Life-Short Form 47 (ITQoL-SF47) for children 2 months-4 years, the Child Health Questionnaire-Parent Form 50 (CHQ-PF50) and PROMIS Pain Interference and Sleep Disturbance Parent Proxy short forms for children 5-11 years, and a study-specific survey of school experiences., Results: Children with SCD 2 months-4 years had lower ITQoL-SF47 scores (ie, worse HRQoL, p<0.001) than a normative sample of children; across domains, differences ranged from 18.73-45.03 points and exceeded minimal important difference (MID) thresholds. Except for the behavior domain, children with SCD 5-11 years had lower scores on all CHQ-PF50 domains than the normative sample (p<0.001); differences ranged from 6.78-36.37 points and exceeded MID thresholds. Children with more frequent VOCs had lower HRQoL and worse school experiences than children with less frequent VOCs (p<0.05, except for behavior domains). The largest differences based on VOC frequency were observed for overall health and bodily pain/discomfort among children 2 months-4 years (differences=40.88 and 32.50 points, respectively), and bodily pain and role/social limitations due to physical health among children 5-11 years (differences=38.99 and 37.80, respectively). Caregivers of children with more frequent VOCs experienced greater burden than caregivers of children with less frequent VOCs, though specific areas of impact (eg, caregiver emotions, time) differed across child age groups., Conclusion: VOC frequency is negatively associated with HRQoL, highlighting the burden experienced by children with SCD and their caregivers., Competing Interests: GPY, JP, SL, and SI are employees of Novartis Pharmaceuticals Corporation. GPY and JP also own stock in the company. AC has received consultancy and research funding from Novartis Pharmaceuticals Corporation. He also reports grants for clinical trial and/or consultancy from Global Blood Therapeutics, Agios, Vertex, and Bluebird Bio, outside the submitted work. AAR and KLM are employees of QualityMetric Incorporated, LLC, and received funding from Novartis Pharmaceuticals Corporation to conduct this research. After the study was conducted, QualityMetric acquired ownership of the HealthActCHQ family of surveys, which includes the CHQ-PF50 and the ITQoL-SF47. The authors report no other conflicts of interest in this work., (© 2023 Campbell et al.)