This study examined the effects of aerobic and resistance training, and their combination on health-related quality of life (HRQoL) in adolescents with overweight or obesity. After a 4-week run-in period, 304 (91 males, 213 females) post-pubertal adolescents aged 14-18 years, were randomized to 4 groups for 22 weeks of: aerobic training (n = 75), resistance training (n = 78), combined aerobic and resistance training (n = 75), or nonexercising control (n = 76). All participants received dietary counseling with a daily energy deficit of 250 kcal. Indicators of HRQoL such as overall HRQoL, and physical and psychosocial (an aggregate of emotional, social, and school functioning) HRQoL at baseline and 6 months postintervention were measured by the Pediatric Quality of Life questionnaire. The trial began in March 2005 and was completed in June 2011. In the intention-to-treat analyses, all groups showed significant improvements at 6 months on all HRQoL indicators. The aerobic group showed greater improvements than controls on physical HRQoL (mean differences of 5.5; 95% CI; 1.4-9.6, p = 0.009). In participants with ≥70% adherence, combined training produced greater improvements than control on overall HRQoL (mean differences of 4.8, 95% CI; 0.7-9.0, p = 0.02), physical HRQoL (mean differences of 5.8; 95% CI: 0.6-10.7; p = 0.03), social HRQoL (mean differences of 7.6; 95% CI: 1.0-14.2; p = 0.02), and school-based HRQoL (mean differences of 7.6; 95% CI: 1.0-14.2; p = 0.02). These findings highlight the potential importance of including resistance exercise into traditional aerobic exercise programs to maximize HRQoL in adolescents with obesity.