Background: The over-the-scope clip (OTSC) provides more durable and full-thickness closure as compared with standard clips. Only case reports and small case series have reported on outcomes of OTSC closure of GI defects. Objective: To describe a large, multicenter experience with OTSCs for the management of GI defects. Secondary goals were to determine success rate by type of defect and type of therapy and to determine predictors of treatment outcomes. Design: Multicenter, retrospective study. Setting: Multiple, international, academic centers. Patients: Consecutive patients who underwent attempted OTSC placement for GI defects, either as a primary or as a rescue therapy. Interventions: OTSC placement to attempt closure of GI defects. Main Outcome Measurements: Long-term success of the procedure. Results: A total of 188 patients (108 fistulae, 48 perforations, 32 leaks) were included. Long-term success was achieved in 60.2% of patients during a median follow-up of 146 days. Rate of successful closure of perforations (90%) and leaks (73.3%) was significantly higher than that of fistulae (42.9%) (P < .05). Long-term success was significantly higher when OTSCs were applied as primary therapy (primary 69.1% vs rescue 46.9%; P = .004). On multivariate analysis, patients who had OTSC placement for perforations and leaks had significantly higher long-term success compared with those who had fistulae (OR 51.4 and 8.36, respectively). Limitations: Retrospective design and multiple operators with variable expertise with the OTSC device. Conclusion: OTSC is safe and effective therapy for closure of GI defects. Clinical success is best achieved in patients undergoing closure of perforations or leaks when OTSC is used for primary or rescue therapy. Type of defect is the best predictor of successful long-term closure.