BACKGROUND: Roux-en-Y gastric bypass (RYGB) is a highly effective treatment for obesity and results in long-term weight loss and resolution of co-morbidities. However, weight regain may occur as soon as 1-2 years after surgery. OBJECTIVES: This retrospective study aimed to investigate the prevalence of weight regain and possible preoperative predictors of this phenomenon after RYGB. SETTING: An academic medical center in the United States. METHODS: A total of 1426 obese patients (15.8% male) who underwent RYGB during January 2000 to 2012 and had at least a 2-year follow-up were reviewed. We included only patients who were initially successful, having achieved at least 50% excess weight loss at 1 year postoperatively. Patients were then categorized into either the weight regain group (WR) or sustained weight loss (SWL) group based upon whether they gained≥15% of their 1-year postoperative weight. RESULTS: Weight regain was observed in 244 patients (17.1%). Preoperative body mass index was similar between groups. Body mass index was significantly higher and percent excess weight loss was significantly lower in the WR group (P<.001). Average weight regain was 19.5±9.3 kg and-.8±8.5 in the WR and SWL groups, respectively (P<.001). Time elapsed since RYGB was significantly longer in the WR group (WR 6.0±2.4 years versus SWL 3.3±1.8 years; P<.001; range 2-12 yr). Patients in the WR group were significantly younger (WR 42.3±9.8 yr versus SWL 45.7±10.8 years; P<.001), had fewer co-morbidities, and were less likely to have type 2 diabetes with insulin dependence preoperatively. Univariate analysis found that older age, male gender, having hypertension, dyslipidemia, and insulin-treated type 2 diabetes were all factors associated with sustained weight loss. Moreover, a longer duration after RYGB was associated with weight regain. Multivariate analysis revealed that younger age was a significant predictor of weight regain even after adjusting for time since RYGB. CONCLUSION: The present study confirmed that a longer interval after RYGB was associated with weight regain. Younger age was a significant predictor of weight regain even after adjusting for time since RYGB. The findings of this study underscore the complexity of the mechanisms underlying weight loss and regain after RYGB. Future prospective studies are needed to further explore the prevalence, predictors, and mechanisms of weight regain after RYGB.