Background/Aims: Endoscopic submucosal dissection (ESD) for superficial non-ampullary duodenal tumors (SNADETs) is associated with a high rate of en bloc resection. However, the technique for ESD remains challenging. Recent studies have demonstrated the effectiveness of S-O clips in colonic and gastric ESD. We evaluated the efficacy and safety of duodenal ESD using an S-O clip for SNADETs. Methods: Consecutive patients who underwent ESD for SNADETs between January 2011 and December 2021 were retrospectively enrolled. Propensity score matching analysis was used to compare patients who underwent duodenal ESD with the S-O clip (S-O group) and those who underwent conventional ESD (control group). Intraoperative perforation rate was the primary outcome, while procedure time and R0 resection rate were the secondary outcomes. Results: After propensity score matching, 16 pairs were created: 43 and 17 in the S-O and control groups, respectively. The intraoperative perforation rate in the S-O group was significantly lower than that in the control group (p=0.033). A significant difference was observed in the procedure time between the S-O and control groups (39±9 vs. 82±30 minutes, respectively; p=0.003). Conclusions The S-O clip reduced the intraoperative perforation rate and procedure time, which may be useful and effective in duodenal ESD.