Importance: Short-term and midterm data suggest that mesenteric defects closure during laparoscopic Roux-en-Y gastric bypass (LRYGB) surgery reduces the risk of internal herniation with small bowel obstruction (SBO) but may increase risk of kinking of the jejunojejunostomy in the early postoperative period. However, to our knowledge, there are no clinical trials reporting long-term results from this intervention in terms of risk for SBO or opioid use. Objective: To evaluate long-term safety and efficacy outcomes of closure of mesenteric defects during LRYGB. Design, Setting, and Participants: This randomized clinical trial with a 2-arm, parallel, open-label design included patients with severe obesity scheduled for LRYGB bariatric surgery at 12 centers in Sweden from May 1, 2010, through November 14, 2011, with 10 years of follow-up after the intervention. Interventions: During the operation, patients were randomly assigned 1:1 to closure of mesenteric defects beneath the jejunojejunostomy and at the Petersen space using nonabsorbable running sutures during LRYGB or to nonclosure. Main Outcome and Measures: The primary outcome was reoperation for SBO. New incident, chronic opioid use was a secondary end point as a measure of harm. Results: A total of 2507 patients (mean [SD] age, 41.7 [10.7] years; 1863 female [74.3%]) were randomly assigned to closure of mesenteric defects (n = 1259) or nonclosure (n = 1248). After censoring for death and emigration, 1193 patients in the closure group (94.8%) and 1198 in the nonclosure group (96.0%) were followed up until the study closed. Over a median follow-up of 10 years (IQR, 10.0-10.0 years), a reoperation for SBO from day 31 to 10 years after surgery was performed in 185 patients with nonclosure (10-year cumulative incidence, 14.9%; 95% CI, 13.0%-16.9%) and in 98 patients with closure (10-year cumulative incidence, 7.8%; 95% CI, 6.4%-9.4%) (subhazard ratio [SHR], 0.42; 95% CI, 0.32-0.55). New incident chronic opioid use was seen among 175 of 863 opioid-naive patients with nonclosure (10-year cumulative incidence, 20.4%; 95% CI, 17.7%-23.0%) and 166 of 895 opioid-naive patients with closure (10-year cumulative incidence, 18.7%; 95% CI, 16.2%-21.3%) (SHR, 0.90; 95% CI, 0.73-1.11). Conclusions and Relevance: This randomized clinical trial found long-term reduced risk of SBO after mesenteric defects closure in LRYGB. The findings suggest that routine use of this procedure during LRYGB should be considered. Trial Registration: ClinicalTrials.gov Identifier: NCT01137201.