Endoscopic ampullectomy (EA) is increasingly used in the management of ampullary neoplasia. Although studies on the safety and efficacy of this procedure exist, no study has specifically addressed the histopathologic features of the specimens. We review our experience with 45 EA specimens assessed for the following: diagnosis, high-grade dysplasia (HGD), submucosal ampullary gland/ductule involvement, specimen integrity, and margin status. Familial adenomatous polyposis (FAP) status and the endoscopist's impression of completeness of removal were also ascertained. Previous biopsy diagnoses were compared with ampullectomy diagnoses, and histologic and clinical features were correlated with disease persistence. The histologic features of the ampullectomy specimens were as follows: diagnosis (no diagnostic abnormality, 3; reactive, 8; adenoma, 26; adenocarcinoma, 7; other, 1); HGD, 1; submucosal ampullary gland/ductule involvement, 20; specimen integrity (intact, 22; fragmented, 23); and margin status (positive, 20; negative, 2; could not be assessed, 12). Five patients had FAP, and EA was deemed complete in 21 (47%). The diagnostic agreement between preampullectomy biopsy and ampullectomy was 64%. Of the patients, 33 (73%) had documented persistent disease. None of the histologic or clinical features had a statistically significant relationship with disease persistence.