Background Surgical repair of endoscopic perforations of the GI tract used to be the standard, but immediate, secure endoscopic closure has become an attractive alternative treatment with the potential to reduce morbidity and mortality. Objective We aimed to perform a systematic review of the medical literature on endoscopic closure of acute iatrogenic perforations of the GI tract. Design A systematic review was conducted according to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-analyses) guidelines. Setting Available medical literature from 1966 through November 2013. Patients Patients with an acute perforation after an endoscopic procedure that was closed endoscopically. Interventions Endoscopic closure of an acute perforation of the GI tract. Main Outcome Measurements Clinically successful endoscopic closure. Results In our search, we identified 726 studies, 702 of which had to be excluded. Twenty-four cohort studies (21 retrospective, 3 prospective) were included in the analysis. No randomized trials were identified. Overall, the methodological quality was low. The 24 studies included described 466 acute perforations in which endoscopic closure was attempted. Successful endoscopic closure was achieved in 419 cases (89.9%; 95% CI, 87%-93%). Successful closure was achieved in 90.2% (n = 359; 95% CI, 87%-93%) of cases by using endoclips, in 87.8% (n = 58; 95% CI, 78%-95%) by using the over-the-scope-clip, and in 100% (n = 2) by using a metal stent. Limitations Low methodological quality of included studies. Conclusion This systematic review suggests that endoscopic perforation closure is a safe and effective alternative for surgical intervention in selected cases; however, the overall methodological quality was low. Prospective, true consecutive studies are needed to define the definitive role of endoscopic closure of perforations.