Endoscopic resection of nonampullary duodenal adenoma is often challenging, and its technique has not yet been standardized. To overcome the practical difficulty of conventional endoscopic mucosal resection, underwater endoscopic mucosal resection (UEMR) was recently developed; therefore, we investigated the effectiveness and safety of UEMR for nonampullary duodenal adenoma. A multicenter, prospective cohort study was conducted at 21 institutions in Japan. We enrolled patients with no more than 2 nonampullary duodenal adenomas ≤20 mm in size, who were planned to undergo UEMR. After UEMR, follow-up endoscopies were scheduled at 2 and 12 months after the procedure, and biopsy specimens were taken from the post-UEMR scars. The primary endpoint was the proportion of patients with histologically proven nonrecurrence at follow-up endoscopy and biopsy. A total of 155 patients with 166 lesions underwent UEMR. One patient with a non-neoplastic lesion in the resected specimen and 10 patients with 10 lesions who were lost to follow-up were excluded. Finally, 144 patients with 155 lesions who received all follow-up endoscopies were analyzed for the primary endpoint. The proportion of patients with proven nonrecurrence was 97.2% (n = 140 of 144; 95% confidence interval, 92.8%-99.1%) which exceeded the predefined threshold value (92%). Two cases of delayed bleeding (1.2%) occurred and they were successfully managed by clips. All recurrences were successfully treated by additional endoscopic treatment. This multicenter, prospective cohort study demonstrated effectiveness and safety of UEMR for nonampullary duodenal adenomas ≤20 mm in size. (University Hospital Medical Network Clinical Trials Registry, Number: UMIN000030414).