A series of 19 duodenal and 16 ampullary neoplasms was studied to determine their pathologic features on endoscopic biopsy, to evaluate the diagnostic accuracy of this procedure, and to assess the usefulness of immunohistochemical staining for carcinoembryonic antigen (CEA) in these neoplasms. The 11 benign neoplasms (31 per cent) were adenomas, five of which had focal hyperplastic features; the 24 malignant neoplasms (69 per cent) included ten intestinal-type carcinomas (resembling colonic carcinoma), seven anaplastic carcinomas (resembling diffuse gastric carcinoma), two adenocarcinomas in situ, and five lesions of unoriented, cytologically malignant epithelium. Malignancy was suspected endoscopically in 19 of 24 carcinomas, and the majority of the benign neoplasms were described as polyps or plaques. Resections (performed in 20 cases) demonstrated the accuracy of the biopsy diagnoses in 17 cases (85 per cent). In the three discordant cases, diagnosed by biopsy as adenoma in two cases and carcinoma in situ in one, coexistent in situ or infiltrating carcinomas were identified in the resected specimens. Carcinoembryonic antigen (20 cases) was identified mostly along glycocalyceal borders in normal and adenomatous tissues, whereas the carcinomas also showed strong cytoplasmic staining for CEA. Endoscopic biopsy is a valuable procedure in the diagnosis of duodenal and ampullary neoplasms. Correlation of the pathologic features of biopsy specimens with endoscopic appearances may result in more accurate diagnoses.