The aims of this study were to compare the effects of weight-loss diets of different macronutrient compositions on weight and health-related quality of life (HRQOL), and to examine the relationship between changes in HRQOL parameters and weight loss during weight-loss programs in obese adolescents. Seventy one adolescents (12-18 years, BMI>95th percentile) were randomly allocated to one of three 12-week diet regimens: low-carbohydrate low-fat (LCLF), low-carbohydrate high-fat (LCHF) or high-carbohydrate low-fat (HCLF) diets. Weight, height and fat-mass were measured, and the PedsQL 4.0 questionnaires were administered to the participants at baseline and at the end of the intervention. Significant similar reductions in BMI, BMI-SDS, and fat percentage occurred in all groups. A significant improvement in HRQOL was found only in the LCLF and HCLF groups. For the entire sample, positive correlations were found between emotional and psychosocial functioning at baseline and the reduction in BMI, BMI-SDS, and fat percentage. By multiple regression analysis, higher baseline emotional functioning and BMI-SDS were significant predictors to higher reduction in BMI-SDS during the intervention. Our results support the importance of evaluating and improving psychosocial functioning before initiation of a weight-loss intervention program in adolescents, and the importance of low-fat diets in weight-loss interventions for adolescents.