Background: The advantages of endoscopic retrograde cholangiopancreatography (ERCP) over traditional surgery for correction of various biliary and pancreatic pathologies became apparent immediately after its introduction into large clinical practice and today are also not in doubt. ERCP and endoscopic sphincterotomy (EST) are characterized by efficacy similar to open surgery, but significantly less traumatic, relatively easy, a decrease in the degree of perioperative surgical and anesthetic risk, and a reduction in the time of in-hospital treatment and postoperative recovery. However, therapeutic ERCP with EST can be complicated by gastrointestinal bleeding, the degree of which can range from mild to very severe and even life-threatening. Although the greatest risk for the development of bleeding after EST is caused by preexisting coagulopathy, the anatomical features of the arterial blood supply to the pancreaticoduodenal region and major duodenal papilla should also be taken into account during the endoscopic procedure. Conclusions: The communicating artery, directly vascularizing the area of the major duodenal papilla, usually originates from the posterior superior pancreaticoduodenal artery, and entering in the anterior pancreaticoduodenal arcade. The smallest number of papillary arteries, distributed in potential accessibility to the sphincterotomy incision, are located in the zone between 10 and 11 o’clock of the papilla Vater circumference. Hence, the preferred performance of EST in this area can be accompanied by a significant reduction in the risk of arterial bleeding after ERCP.