The study objectives were to assess 2-year changes in health-related quality of life (HRQL) after gastric bypass in patients with severe obesity and to analyze HRQL improvements in relation to weight loss after bariatric surgery. This was a prospective intervention study with consecutive patients referred to two bariatric surgical units in the Basque Country. We used both generic (Short Form Health Survey, SF-36 and EuroQol, EQ-5D), and specific questionnaires (Moorehead-Ardelt, MA II and Obesity-related Problems Scale, OP). Effect sizes and receiver operating characteristic (ROC) curves were calculated to assess the change in quality of life. Spearman's correlation coefficient was calculated to assess whether there was an association between changes in body mass index (BMI) and HRQL. Of 82 patients who underwent surgery, 79 were followed-up for 2 years. Mean weight loss was 37% of body weight (49 kg) and BMI fell from 50.6 to 31.8. The initial problems and final improvements were greater in the physical dimensions. Considerable benefits were observed in assessments with all the instruments used. However, the changes in weight/BMI and HRQL were not linear. The comparison with general population showed a similar profile in SF-36 dimensions after surgery. Severely obese patients have lower perceived health across all dimensions of quality of life. Moreover, the impact on functioning is so important that severe obesity can be described as a cause of disability that disappears 2 years after surgical treatment. ROC curves indicate that most of the HRQL measures are poor predictors of change in terms of reduction in body weight or BMI.