BACKGROUND: Few studies have evaluated the long-term outcomes of bariatric surgery patients in relation to obese individuals not participating in weight loss interventions. Our objective was to evaluate the 6-year changes in health-related quality of life (HRQOL) in gastric bypass (GB) patients versus 2 obese groups not undergoing surgical weight loss. The study setting was a bariatric surgery practice. METHODS: A total of 323 GB patients were compared with 257 individuals who sought but did not undergo gastric bypass and 272 population-based obese individuals using weight-specific (impact of weight on quality of life-lite) and general (medical outcomes study short-form 36 health survey) HRQOL questionnaires at baseline and 2 and 6 years later. RESULTS: At 6 years, compared with the controls, the GB group exhibited significant improvements in all domains of weight-specific and most domains of general HRQOL (i.e., all physical and some mental/psychosocial). The 6-year percentage of excess weight loss correlated significantly with improvements in both weight-specific and physical HRQOL. The HRQOL scores were fairly stable from 2 to 6 years for the GB group, with small decreases in HRQOL corresponding to some weight regain. CONCLUSIONS: GB patients demonstrated significant improvements in most aspects of HRQOL at 6 years compared with 2 nonsurgical obese groups. Despite some weight regain and small decreases in HRQOL from 2 to 6 years postoperatively, the HRQOL was relatively stable. These results support the effectiveness of weight loss achieved with gastric bypass surgery for improving and maintaining long-term HRQOL.