Objective: To investigate the potential of prophylactic closure of mucosal defects to prevent adverse events following endoscopic resection of superficial layers of the gastrointestinal (GI) wall.Design: Systematic review and meta-analysis.Data sources: We searched PubMed, Embase, Web of Science and the Cochrane Library for studies eligible for inclusion in our meta-analysis from inception to February 2022.Data extraction and synthesis: We compared the effects of closure versus non-closure of mucosal defects with respect to adverse events including delayed bleeding, delayed perforation and postpolypectomy coagulation syndrome (PPCS). We used a random-effects model for all analyses. Subgroup analyses were performed based on gastrointestinal sites, surgical procedures and study designs.Results: In total, this study includes 11 383 patients from 28 studies. For delayed bleeding, closure group was associated with a lower incidence (Risk Ratio [RR]: 0.40, 95% Confidence interval [CI]: 0.30 to 0.53, p<0.001; I²=25%) and consistent results were observed in the subgroups. Also, for delayed perforation, a combined analysis of all sites and surgical methods showed a protective effect of prophylactic closure of mucosal defects (RR: 0.42, 95% CI: 0.22 to 0.82, p=0.01; I²=0%). Similar results were observed in the subgroup analyses, despite the wide CIs. Regarding the PPCS, neither the pooled RRsnor the subgroup analyses showed significant differences.Conclusion: Prophylactic closure of mucosal defects is beneficial in reducing the incidence of delayed bleeding and delayed perforation after endoscopic resection, but there is no significant difference in reducing the incidence of PPCS.