BACKGROUND: Few prospective studies compare long-term health-related quality of life (HRQOL) outcomes between bariatric surgery patients and individuals with severe obesity who do not undergo bariatric surgery. OBJECTIVES: This 12-year, prospective study evaluated the trajectory and durability of HRQOL changes in gastric bypass patients (surgery group; n = 418) and compared these changes to 2 nonsurgical groups. The nonsurgery group 1 (n = 417) sought but did not have surgery; nonsurgery group 2 (n = 321) had severe obesity but did not seek surgery. SETTING: Bariatric surgery center. METHODS: Weight-related (impact of weight on quality of life-lite [IWQOL-Lite]) and general (short-form health survey-36 [SF-36]) HRQOL questionnaires were administered at baseline and 2, 6, and 12 years postsurgery. RESULTS: At 12 years, the surgery group showed greatly improved weight-related HRQOL (IWQOL-Lite) and physical HRQOL (physical component summary of short-form health survey-36) from baseline, and differences between the surgery group and both nonsurgery groups were significant for IWQOL-Lite and physical component summary. IWQOL-Lite and physical component summary scores peaked at 2 years, followed by declines from 2 to 6 and 6 to 12 years. Small improvements in mental/psychosocial aspects of HRQOL (mental component summary of short-form health survey-36) seen in the surgery group at 2 years were not maintained at either 6 or 12 years. CONCLUSIONS: Gastric bypass patients demonstrated significantly higher weight-related and physical HRQOL at 12 years compared with their very low baseline scores, with the trajectory peaking at 2 years. Despite declining HRQOL between 2 and 12 years, the magnitude of improvement supports the clinical relevance of bariatric surgery for enhancing patients' quality of life.