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Background and Aims: Endoscopic resection of duodenal non-lifting adenomas and subepithelial tumors is challenging and harbors a significant risk of adverse events. We report on a novel technique for duodenal endoscopic full-thickness resection (EFTR) by using an over-the-scope device., Methods: Data of 4 consecutive patients who underwent duodenal EFTR were analyzed retrospectively. Main outcome measures were technical success, R0 resection, histologic confirmation of full-thickness resection, and adverse events. Resections were done with a novel, over-the-scope device (full-thickness resection device, FTRD)., Results: Four patients (median age 60 years) with non-lifting adenomas (2 patients) or subepithelial tumors (2 patients) underwent EFTR in the duodenum. All lesions could be resected successfully. Mean procedure time was 67.5 minutes (range 50-85 minutes). Minor bleeding was observed in 2 cases; blood transfusions were not required. There was no immediate or delayed perforation. Mean diameter of the resection specimen was 28.3 mm (range 22-40 mm). Histology confirmed complete (R0) full-thickness resection in 3 of 4 cases. To date, 2-month endoscopic follow-up has been obtained in 3 patients. In all cases, the over-the-scope clip was still in place and could be removed without adverse events; recurrences were not observed., Conclusions: EFTR in the duodenum with the FTRD is a promising technique that has the potential to spare surgical resections. Modifications of the device should be made to facilitate introduction by mouth. Prospective studies are needed to further evaluate efficacy and safety for duodenal resections., (Copyright © 2015 American Society for Gastrointestinal Endoscopy. Published by Elsevier Inc. All rights reserved.)