Periampullary bleeding is an uncommon cause of upper gastrointestinal (GI) hemorrhage, which is typically iatrogenic in origin occurring as the result of endoscopic intervention of the papilla. Spontaneous, non-iatrogenic periampullary bleeding is extraordinarily rare with only a few cases reported in the literature to date. Vascular malformations, including angiodysplasia and Dieulafoy's lesions, have been implicated in several reports as the etiology but endoscopic intervention is often unsuccessful in achieving durable hemostasis with surgery being required for definitive management in many cases. Herein is reported the case of a 67-year-old male on anticoagulation for atrial fibrillation who presented with severe upper GI bleeding determined to be arising from underneath the hood of the major papilla. No distinct lesion was seen endoscopically but the presumed etiology was an unidentified vascular malformation. Successful treatment was achieved with argon plasma coagulation (APC) applied circumferentially around the papilla. No subsequent endoscopic or surgical intervention was required for durable hemostasis and the patient was able to resume anticoagulation shortly after the procedure. This is the first reported case of spontaneous periampullary bleeding successfully treated with APC.