Endoscopic resection of over 3/4 of the lumen of the antrum or pylorus is a known risk factor for post-endoscopic submucosal dissection (ESD) stenosis. Local or systemic steroids may reduce the risk of stenosis, but their overall role in stenosis prevention remains controversial. We aimed to evaluate the efficacy and safety of prophylactic gastric open peroral endoscopic myotomy (GO-POEM) in preventing post-ESD stenosis. Methods: Ten patients who underwent GO-POEM during or immediately after ESD in the Presbyterian Medical Center between June 2017 and November 2020 were included. All patients underwent excision of over 3/4 of the lumen of the antrum or pylorus. GO-POEM was performed without submucosal tunneling.Results: Well-differentiated tubular adenocarcinoma, tubulovillous adenoma with high-grade dysplasia, and tubular adenoma with low-grade dysplasia were diagnosed in three, one, and six patients, respectively. GO-POEM was performed successfully in all the 10 patients. Stenosis could not be evaluated in one patient, whereas one of the remaining nine patients developed post-ESD stenosis. GO-POEM decreased the risk of post-ESD stenosis in the other eight patients. Two patients presented with intraprocedural bleeding, both of whom were managed endoscopically successfully.Conclusions: Prophylactic GO-POEM may be a novel, effective and safe treatment modality for preventing post-ESD stenosis in the stomach. Well-designed, multicenter studies with large sample sizes are needed to confirm our results.