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This study aimed to demonstrate the feasibility and safety of a novel twin-grasper assisted mucosal inverted closure (TAMIC) technique for large perforations after gastric endoscopic full-thickness resection (EFTR) in a porcine model.Iatrogenic large perforations of stomach were created and closed by an experienced endoscopist using TAMIC technique in 12 pigs. Repeat gastroscopy was performed in 4 weeks after surgery to examine the wound sites and then the animals were sacrificed. The primary outcomes were the successful TAMIC closure rate and the complete healing rate. Secondary end points included procedure time of TAMIC, complete inverted healing rate, delayed bleeding rate and post-surgery perforation. Histologies of the wounds were analyzed by hematoxylin-eosin, masson trichrome and immunohistochemistry staining.The median size of the defects was 3.5 (range 2.5 - 4.5) cm. TAMIC was successfully performed in all the 12 pigs. Complete healing was achieved in 11 pigs 4 weeks after operation as one pig died post-surgery due to severe pneumonia. The median procedure time for TAMIC was 39 (range 23 - 81) min. The complete inverted healing rate was 45.5% (5/11). No delayed bleeding or post-surgery perforation was observed. Histologic analyses showed that both the epithelium and muscularis mucosae layers were appropriately connected under inverted healing.TAMIC is feasible and safe for closure of large perforations after gastric EFTR and could be a propagable and promising technique for clinical practice.