To examine the effect of treatment-induced weight loss on Health-Related Quality of Life (HRQL), 38 mildly-to-moderately overweight persons recruited to participate in a study to examine the efficacy of a lifestyle modification treatment program completed a sociodemographic questionnaire, the Beck Depression Inventory (BDI), the Medical Outcomes Study Short-Form Health Survey (SF-36, as an assessment of HRQL), and underwent a series of clinical evaluations prior to treatment. After baseline evaluations, participants were randomly assigned to either a program of lifestyle physical activity or a program of traditional aerobic activity. Participants again completed the SF- 36 and BDI after the 13-week treatment program had ended. Weight loss averaged 8.6 ± 2.8 kg over the 13-week study. We found that weight loss was associated with significantly higher scores (enhanced HRQL), relative to baseline, on the physical functioning, role-physical, general health, vitality and mental health domains of the SF-36. The largest improvements were with respect to the vitality, general health perception and role- physical domains. There were no significant differences between the lifestyle and aerobic activity groups on any of the study measures. These data indicate that, at least in the short-term, weight loss appears to profoundly enhance HRQL.