BACKGROUND/AIMS: Clip closure of mucosal defects after colorectal endoscopic submucosal dissection (C-ESD) may decrease the incidence of delayed adverse events. The size of the defect to be closed by conventional clip is limited, however, and we sometimes encounter incomplete closure when the defect is located at the flexure. As, theoretically, underwater clip closure (UCC) could achieve complete closure despite these difficult cases, we investigated its feasibility. METHODS: We retrospectively analyzed 21 patients who underwent UCC after C-ESD. The main outcome was the UCC success rate, defined as complete closure of the defect. Other outcomes were procedure time, number of clips, and the delayed adverse event rate. RESULTS: The median resected specimen size was 31 mm (range 18-47 mm). The UCC success rate was 100%. The median procedure time was only 11 min (range 6-21 min). The median number of clips was 9 (range 5-16). No delayed adverse event occurred. CONCLUSION: It is feasible to use UCC to close large mucosal defects, although further studies are warranted to assess its efficacy.