Objective: To compare health-related quality of life (HRQoL) in children with prune-belly syndrome (PBS) and their caregivers to healthy controls, as children and adolescents with PBS face numerous potential physical and psychosocial challenges. Materials and Methods: Study participants completed the Pediatric Quality of Life Inventory Generic Core Scales (PedsQL) 4.0 generic core scales (children) or Quality of Life Enjoyment and Satisfaction Questionnaire Short Form (Q-LES-Q-SF) (caregivers) in an online, anonymous format. The PedsQL 4.0 is a 23-item, age-adjusted, validated questionnaire that assesses physical, emotional, social, and school functioning in pediatric patients. The Q-LES-Q-SF is a validated, self-report measure that assesses various areas of daily functioning in adults. Results: PedsQL 4.0 was completed by 32 children with PBS. Individual physical (66.3 ± 20 vs 84.4 ± 17.3; P < .0001), emotional (68.4 ± 23.4 vs 80.9 ± 19.6; P < .01), social (63.1 ± 21.3 vs 87.4 ± 17.2; P < .0001), and school (53 ± 21.7 vs 78.6 ± 20.5; P < .0001) functioning scales were all significantly lower than in healthy children. Nineteen caregivers completed the Q-LES-Q-SF. Caregivers had a mean raw score of 54.8 ± 9.6, which was significantly lower (P = .02) than the comparative healthy adult cohort (59.8 ± 11.3). Conclusion: PBS profoundly impacts HRQoL in children, negatively affecting physical, emotional, social, and school functioning. Caregivers of PBS patients also report an overall lower quality of life, highlighting the challenges that families with chronically ill children often face.