OBJECTIVES: To compare health-related quality of life (HRQOL) in a group of pediatric patients with congenital heart disease (CHD) and healthy controls and patients with other chronic diseases, and to compare HRQOL among patients with CHD of various severity categories with one another, with controls, and with patients with other chronic diseases. STUDY DESIGN: In this cross-sectional survey, t tests were used to compare patient and proxy-reported Pediatric Quality of Life Inventory 4.0 Generic Core Scales (PedsQL) scores (including total, physical health, and psychosocial health summary scores) in children (aged 8-12 years) and adolescents (aged 13-18 years) between controls and (1) a composite CHD population; and (2) patients in each of 3 CHD severity categories: mild (no intervention), biventricle (BV; postintervention), and single ventricle (SV; postpalliation). PedsQL scores among CHD severity categories were compared by ANOVA. PedsQL scores were also compared in the CHD population and children with other chronic diseases without age stratification using t tests. RESULTS: There were 1138 (children, n = 625; adolescents, n = 513) and 771 (children, n = 528; adolescents, n = 243) patient and/or proxy reporters in the CHD and healthy control groups, respectively. Total, physical health, and psychosocial health summary scores were lower in the composite CHD, BV, and SV groups compared with controls (P < .0001). There were significant differences among disease severity categories for all scores (P < .01). The composite CHD, BV, and SV groups had similar PedsQL scores as end-stage renal disease, asthma, and obesity populations. CONCLUSION: Children and adolescents with BV and SV CHD have significantly lower HRQOL than healthy controls and similar HRQOL as patients with other chronic pediatric diseases. Interventions targeting both physical and psychosocial domains are needed to improve HRQOL in this high-risk population.