BACKGROUND AND AIMSA novel gastroduodenal full-thickness resection device system was developed for resection of upper gastrointestinal (GI) tract lesions. Our study aimed to evaluate the efficacy and safety of the gastroduodenal full-thickness resection device system. METHODSConsecutive patients who received endoscopic resection of upper GI tract lesion (6/2020-8/2022) using gastroduodenal full-thickness resection device were evaluated from eight U.S. centers. Primary endpoints included technical success and R0 resection. Secondary endpoints were en bloc resection, residual lesions at follow-up endoscopy, and immediate/delayed adverse events. RESULTSForty-four patients (mean age 60.9±15.8 years) received 45 resections for gastric (35, 80%) and duodenal (9, 20%) leions. 34 (77%) were subepithelial and 10 (23%) were epithelial lesions. Technical success and en bloc resection were achieved in 43 (96%) and 41 (91%) patients, respectively. Furthermore, R0 resection was achieved in 32 (71%) patients including 24 (69%) of 35 with neoplastic lesions. Pathologic diagnosis included neuroendocrine tumor in 14 (32%), gastrointestinal stromal tumor in 10 (23%), and gastric cancer/high grade dysplasia in 7 (16%). Minor immediate and delayed bleeding occurred in 17 (38%) and 2 (4%) patients. One patient had delayed perforation, managed conservatively. On follow-up, 19 (90%) of 21 patients had no residual lesion. CONCLUSIONIn this multicenter series, gastroduodenal full-thickness resection device demonstrated high rates of technical success and acceptable rate of R0 resection. Immediate minor bleeding was common, while serious adverse events were rare. Gastroduodenal full-thickness resection device should be considered in patients with gastroduodenal subepithelial lesions as an alternative to long-term surveillance.