PURPOSE: Phentermine/topiramate combination therapy resulted in significant weight loss and improvements in cardiometabolic risk factors in patients with obesity/overweight in two published 56-week randomized, placebo-controlled trials (EQUIP and CONQUER). The purpose of the current study was to examine whether phentermine/topiramate is also associated with greater improvements in health-related quality of life (HRQOL) and whether HRQOL improvements are solely attributable to weight reduction. METHODS: Patients in EQUIP (n = 751) had a body mass index (BMI) ≥ 35 with no obesity-related comorbidity. Patients in CONQUER (n = 1623) had a BMI ≥ 27 and ≤ 45 and at least two obesity-related comorbid conditions. HRQOL was assessed with Impact of Weight on Quality of Life-Lite (IWQOL-Lite) and Medical Outcomes Study Short Form (SF-36) (CONQUER only). RESULTS: Significant improvements in both obesity-specific and physical HRQOL were observed at 56 weeks in both trials (p < .0001). In EQUIP, BMI reduction fully mediated improvements in IWQOL-Lite total score (p < .0001). In CONQUER, both BMI reduction (all p values < .0001) and change in depressive symptoms (all p values < .025) were significant mediators of improved IWQOL-Lite total score and SF-36 Physical Component Summary score. Gender, psychiatric history, and baseline triglycerides moderated these relationships. CONCLUSIONS: Both trials demonstrated that treatment with phentermine/topiramate improved HRQOL compared with placebo. Although reduction in BMI accounted for the majority of improvements in obesity-specific and physical HRQOL, decrease in depressive symptoms was also a significant mediator. Results highlight the predominance of weight reduction as a key factor in improving HRQOL in obesity.