INTRODUCTION AND OBJECTIVES: Endoscopic ampullectomy is the preferred treatment for selected periampullary lesions, yet up to 10.6% of patients may experience delayed bleeding post-procedure. This study aims to identify predictors for bleeding, which remain poorly understood. METHODS: This was a single-center retrospective cohort study of adult patients who underwent endoscopic ampullectomy (EA) between January 2011 and September 2023. The primary outcome was the risk factors for delayed bleeding, defined as post-procedural bleeding that necessitated either an emergency department visit, hospital admission, blood transfusion, or re-intervention. Secondary outcomes included adverse events, such as perforation and pancreatitis. RESULTS: A total of 113 patients underwent EA, and 25 (22.1%) experienced delayed bleeding. Of these, 20 (80%) required repeat endoscopy, six (24%) needed blood transfusions, and three (12%) were managed conservatively. Multivariable logistic regression analysis identified international normalized ratio ≥1.2 (odds ratio [OR] 3.32, 95% confidence interval [95% CI] 1.03-10.74, CONCLUSION: Several factors, including features of high-grade dysplasia-intramucosal cancer, international normalized ratio ≥1.2, female sex, lesion size, and procedure duration are associated with delayed post-ampullectomy bleeding. These factors should be taken into consideration when strategizing the reduction of post-ampullectomy bleeding.