Effect of bariatric surgery on health-related quality of life (HRQOL) varies greatly. This might be caused by the diversity in questionnaires used to assess HRQOL and the weight loss of the studied population. This study assesses the relationship between weight loss and HRQOL in primary Roux-en-Y gastric bypass (RYGB) patients by using an obesity-specific (impact of weight on quality of life-lite, IWQOL-lite) and a generic (RAND-36) questionnaire. HRQOL and weight parameters were assessed before and 15 and 24 months after RYGB surgery. HRQOL was assessed by using IWQOL-lite (an obesity-specific questionnaire consisting of one total score and five domains) and RAND-36 (a generic questionnaire consisting of two subtotal scores, the physical health summary (PHS) and mental health summary (MHS), and nine scales). Two thousand one hundred thirty-seven patients were included. HRQOL improved significantly after RYGB. Preoperative BMI was negatively related to baseline PHS (p < 0.001) and IWQOL-lite total (p < 0.001). Percentage total weight loss (%TWL) was positively related to HRQOL score at both follow-up moments. Change in HRQOL from baseline to 24 months was related to %TWL at 24 months in both subtotals of RAND-36 and IWQOL-lite total score (p ae0.001 in all). HRQOL improves after RYGB. Higher %TWL is related to greater improvement in HRQOL and better HRQOL 15 and 24 months after RYGB. The variance in the effect of RYGB surgery on HRQOL can be explained by the questionnaire used and weight loss of the population.