Objectives: There are limited reports on the safety of gastrointestinal endoscopic procedures in individuals taking edoxaban, one of the direct oral anticoagulants. We clarified the incidence of delayed bleeding in patients who were on edoxaban in the perioperative period of gastrointestinal endoscopic procedures with a high risk of bleeding., Methods: This was an investigator-initiated, single-center, open-label, prospective, single-arm study. Patients on warfarin or edoxaban undergoing endoscopy with a high risk of bleeding were enrolled from June 2018 to September 2021. Warfarin was replaced with edoxaban in patients on warfarin. Patients taking other direct oral anticoagulants, and antiplatelet drugs, were excluded. The primary endpoint was severe delayed bleeding (Common Terminology Criteria for Adverse Events [CTCAE] grades III-V) and the secondary endpoints included thromboembolism, all adverse events, any delayed bleeding (CTCAE grades I or II), and hospital stay durations., Results: Twenty-one patients on edoxaban underwent high-risk endoscopy. Three cases (14%) experienced CTCAE grade III delayed bleeding, requiring endoscopic hemostasis. No CTCAE grade I-II delayed bleeding or thromboembolic events occurred. Cholangitis and aspiration pneumonia (conservatively treated) occurred during the hospital stay. The median length of hospital stay was 8 days (range 3-24 days). Patients with delayed bleeding had higher systolic blood pressure at admission and longer hospital stays., Conclusions: The delayed bleeding incidence in high-risk endoscopic procedures for patients on edoxaban was acceptable. Higher blood pressure may be associated with increased risk, but further research is needed., Competing Interests: Ken‐ichi Mizuno received honoraria from Daiichi‐Sankyo, Takeda Pharmaceutical, Olympus, Fujifilm, Miyarisan Pharmaceutical, and Nipro. Shuji Terai received research grants from Interstem, ASKA Pharmaceutical, Tsumura, CHIOME Bioscience, BioMimetics Sympathies, Nihon Pharmaceutical, Sysmex, Tosoh, Rohto, Stemrim, Shionogi, Kowa, Gilead Sciences, Abbott, AbbVie, Sumitomo Pharma, Takeda Pharmaceutical, Nippon Kayaku, Otsuka Pharmaceutical, Eisai, EA Pharma, and Asahi Kasei Pharma, and honoraria from Diichi‐Sankyo, Takeda Pharmaceutical, ASKA Pharmaceutical, Gilead Sciences, MSD, and Otsuka Pharmaceutical. The other authors declare no conflict of interest., (© 2024 The Author(s). DEN Open published by John Wiley & Sons Australia, Ltd on behalf of Japan Gastroenterological Endoscopy Society.)