Background Endoscopic resections in the duodenum harbor a significant risk of complications. The full-thickness resection device (FTRD) has shown favorable results concerning efficacy and safety in the resection of colorectal lesions. Data of its use in the duodenum are limited to a single, small case series (n = 4). Methods Data of all consecutive patients scheduled for endoscopic full-thickness resection (EFTR) of duodenal lesions by FTRD in our institution were collected and analyzed retrospectively. Primary endpoint was technical success. Results Between March 2014 and June 2017 EFTR of a duodenal lesion was planned in a total of 20 patients. Overall technical success was 17/20 (85.0%). Indication for EFTR was: adenomas (n = 13, seven treatment naïve, six pretreated), subepithelial tumors (n = 5) and T1 adenocarcinoma (n = 1). The FTRD could be advanced to the lesion in 19/20 cases (95.0%). R0-resection rate was 12/19 (63.2%). During follow-up after 3 and 12 months there were two recurrent adenomas that were successfully re-resected by FTRD. Minor bleedings occurred at the first postinterventional day in 3/19 (15.8%). There were no major bleedings and perforations. Conclusion This study confirmed the feasibility of duodenal EFTR and indicates good efficacy and safety. Larger studies are needed to further investigate this novel technique.