Abstract Objectives To investigate changes in health-related quality of life (HRQOL) 24 months after an inpatient weight-loss program, and examine concurrent changes in body mass index (BMI) and physical activity. Study design This prospective study included 707 overweight and obese 14±2 year olds (57% girls) participating in a 4-6week inpatient weight-loss program, of whom 381 completed a 24 month follow-up. HRQOL, physical activity and BMI were assessed at baseline, discharge, and six, 12 and 24 months after starting therapy. Longitudinal analyses were conducted using repeated measures mixed models, adjusted for age, sex and baseline outcome and accounted for attrition over time. Results At 24 months, overall HRQOL indicated significant improvements relative to baseline (3 points on a 0-100 scale; 95% CI. 1.68 to 4.47; p<0.001). Of the six HRQOL domains, the greatest improvement was observed for self-esteem (11 points; 95% CI. 8.40 to 13.14; p<0.001). BMI was 0.5 kg/m2 lower than baseline (95% CI. -0.92 to -0.02; p=0.04). Long-term changes in physical activity explained 30% of the variation in overall HRQOL (p=0.01), and change in BMI was not associated with change in HRQOL. Conclusions An inpatient weight-loss program was associated with positive changes in HRQOL over the long-term with particular improvements in self-esteem. The results indicate the potential role of physical activity in improving HRQOL without a substantial change in body composition.