Objective: To examine changes in generic and weight-related, health-related quality of life (HRQoL) in children and adolescents with severe obesity participating in intensive lifestyle treatment, and to examine whether changes in SDS-BMI were associated with changes in HRQoL. Methods: In this prospective observational study, a referred sample of 120 children and adolescents (8-19 years) with severe obesity (SDS-BMI ≥ 3.0, or ≥ 2.3 in combination with obesity-related comorbidity) received an intensive 1-year lifestyle treatment with an inpatient period in a specialized childhood obesity center. A weight-related (IWQOL-Kids) and three generic (KIDSCREEN-52, PedsQL 4.0, and EuroQol) HRQoL questionnaires were administered at baseline (T0), after treatment (T1), and 1 year later (T2). Generalized Linear Mixed Models and partial correlations were used to analyze changes in HRQoL and associations with changes in SDS-BMI. Results: Statistically significant improvements in generic and weight-related HRQoL overall and domain scores were observed at T1and at T2 in comparison with T0, despite partial weight regain from T1 to T2. Larger weight loss at T2 was correlated with larger improvements in physical HRQoL domains. Conclusion: Children and adolescents with severe obesity experienced long-term improvements in generic and weight-related HRQoL after participating in intensive lifestyle treatment, despite partial weight regain.