OBJECTIVE: Endoscopic sphincterotomy (EST), especially when anticoagulants are used, carries a significant risk of delayed bleeding. However, the relationship between the use of antithrombotic agents, including direct oral anticoagulants, and post-EST bleeding remains unclear. This study aimed to identify the risk factors for post-EST delayed bleeding when antithrombotic agents were administered according to the guidelines. METHODS: We analyzed cases of patients who underwent endoscopic retrograde cholangiopancreatography and EST between January 2018 and August 2022, focusing on those with normal anatomy and naïve papillae. We examined the incidence of post-EST bleeding, endoscopic retrograde cholangiopancreatography procedure details, severity and timing of post-EST delayed bleeding, hemostatic interventions, and factors related to post-EST delayed bleeding. RESULTS: Among the 502 patients included, 76 (15%) were taking antithrombotic agents. Post-endoscopic retrograde cholangiopancreatography delayed bleeding was noted in seven patients (1.4%). Mild, moderate, and severe delayed bleeding occurred in four, one, and two cases, respectively. Hemostatic injection completely controlled cases of delayed bleeding. Multivariate analysis identified a 1-day direct oral anticoagulants interruption (odds ratio: 20.5, 95% confidence interval: 3.33-125, CONCLUSION: A 1-day direct oral anticoagulants interruption and dialysis are independent risk factors for post-EST delayed bleeding, necessitating careful consideration.