Background: Non-neoplastic conditions of the ampulla of Vater are poorly understood. Our purpose was to investigate non-neoplastic lesions of the ampulla of Vater in relation to past medical history and findings at presentation. Method: Medical records of patients with biopsies of the ampulla of Vater revealing non-neoplastic histopathology in a 5-year period were reviewed after identification from review of our pathology database. Biopsies were reviewed blindly and categorized as “inflammatory”, “reactive, consistent with a site of healing ulcer”, and “acute ulcer”. Results: The mean age of patients was 59 years. Of a total of 26 cases - 14 were male. 11 specimens had nonspecific inflammatory changes, 11 were consistent with a site of healing ulcer, and 4 revealed acute ulceration. Of 14 patients without a history of instrumentation, 5 (36%) showed nonspecific inflammation, 8 (57%) showed changes consistent with a site of healing ulcer, 1 (7%) had acute ulceration. In this subgroup, 9 (64%) had clinical and/or radiographic evidence of biliary obstruction, 6 (43%) had a history of pancreatitis, 5 (36%) had elevated bilirubin and/or alkaline phosphatase, and 3 (21%) had elevated amylase and/or lipase. Twelve of 26 patients (46%) had a recent history of instrumentation in the ampulla of Vater. Nine (75%) of these had either inflammation or changes consistent with site of healing ulcer; 3 (11%) had acute ulceration. No correlation with NSAID use was found. Discussion: This study reveals that a history of instrumentation of the ampullary region is the single most common clinical parameter in patients with non-neoplastic lesions of the ampulla. However, over 50% of patients in this study had no history of instrumentation. Obstructive biliary disease is the common clinical parameter in this subgroup occurring in 9 of 14 patients. Pancreatitis is the second most significant clinical parameter occurring in 6 of 14 patients (43%). Patients with noniatrogenic causes of ampullary inflammation commonly present with obstructive biliary disease or pancreatitis.