Background Routine closure of mesenteric defects is generally considered standard part of laparoscopic gastric bypass surgery today. Controversy still exists regarding the optimal method for mesenteric defects closure. The objective was to compare different methods for mesenteric defects handling in laparoscopic gastric bypass surgery. Methods Primary laparoscopic gastric bypass procedures from 2010 until 2015 reported to the Scandinavian Obesity Surgery Registry (SOReg), where the mesenteric defects closure method was identifiable, were included. Main outcome measures were serious postoperative complication within 30 days after surgery, and reoperation for small bowel obstruction within 5 years after surgery. Quality-of-life before and after surgery, duration of surgery, and risk factors for complication were also analyzed. Information on operation for small bowel obstruction was based on data from the SOReg, the Swedish National Patient Register and reviews of hospital charts. Results In all, 34,707 patients were included. Serious postoperative complication occurred in 174 (2.9%) patients with sutures, in 592 (3.1%, adjusted p = 0.079) with clips, and 278 (3.1%; adjusted p = 0.658) in the non-closure group. Reoperation for small bowel obstruction within 5 years after surgery was lower with sutures (cumulative incidence 6.9%) and clips (cumulative incidence 7.3%; adjusted HR 1.16, 95% CI 1.02-1.32, p = 0.026), compared to non-closure (cumulative incidence 11.2%; adjusted HR 1.63, 95% CI 1.44-1.84, p < 0.0001). Conclusion Closure of the mesenteric defects using either non-absorbable metal clips or non-absorbable running sutures is a safe and effective measure to reduce the risk for small bowel obstruction after laparoscopic gastric bypass surgery. Sutures appear slightly more effective and should remain gold standard for mesenteric defects closure.