Background and aims The duodenum is considered a challenging area for the endoscopic resection of lesions. This study aimed to evaluate the efficacy and safety of over-the-scope clip (OTSC)-assisted endoscopic full-thickness resection (EFTR) for complex nonampullary duodenal lesions unsuitable for conventional resection techniques. Methods and patients We conducted a retrospective case review of 13 consecutive patients with complex nonampullary duodenal tumors that were unsuitable for conventional resection techniques; these patients underwent EFTR assisted with OTSC at Beijing Friendship Hospital, Capital Medical University from September 2015 to September 2020. The OTSC device was placed, and tumors were resected after the lesions were identified. Data were abstracted for demographics, lesion features, histopathologic diagnoses, technical success rates, complete resection (R0 resection) rates, and complications. Results Thirteen patients with duodenal lesions (6 adenomas and 7 submucosal tumors with nonlifting signs, incomplete lifting signs, difficult locations, failed ESD/EMR attempts or suspected origin in the muscularis propria) subjected to EFTR were included. The sizes of all the lesions evaluated by endoscopy were smaller than 20 mm, and most of them (84.6%, 11/13) were smaller than 12 mm. All 13 applications of the clips, endoscopic resection and full-thickness resection were successful (13/13, 100%). Complete resection was achieved in 12 patients (12/13, 92.3%). There were no immediate or delayed complications, including bleeding, infection and perforation. Conclusions OTSC -assisted EFTR appears to be effective and safe for complex nonampullary duodenal lesions smaller than 20 mm (particularly those <= 10-12 mm) that are unsuitable for conventional resection techniques.