This study was designed to evaluate prospectively oncological factors determining survival after resection of tumors of the papilla, comparing local and radical oncological resection. We hypothesized that, in malignant lesions of the ampulla, the T and N stages are major determinants of the patient's long-term outcome. The frequency of malignant lesions in adenomas of the papilla is about 26%. Villous adenoma of the ampulla is considered a premalignant lesion. Local excision has been recommended for benign adenoma and pancreatoduodenectomy for malignant lesions. From January 1, 1982, through June 30, 1997, 171 patients with tumors of the ampulla of Vater were surgically treated. Demographics, intraoperative factors, tumor pathological findings, and postoperative short- and long-term follow-up data were documented prospectively. Of the patients, 45 had adenoma of the papilla and 126 had malignant lesions of the ampulla. Local resection was performed in 40 of the 45 patients with adenoma. In 98 of the 126 patients with malignant lesions, a radical Kausch-Whipple resection or pylorus-preserving pancreatoduodenectomy was used. Of the patients with benign adenoma, 40 had local resection and 5 had pylorus-preserving pancreatic head resection, with a hospital mortality of 0%. Thirty of 35 patients had villous adenoma, 9 (30%) of the 30 with severe dysplasia. Of the 126 patients with malignant lesions, 98 had partial pancreatoduodenectomy and 10 had ampullectomy, with an overall hospital mortality of 3.1% for patients who underwent resection. Seventy-eight of the 98 patients had an R0 resection. The 5-year survival probability for all patients who underwent resection was 84% for cancer stage I, 70% for stage II, and 27% for stage III. In 8 patients with villous adenoma and carcinoma in situ and in 10 patients with cancer in the adenoma, ampullectomy with local lymph node dissection was performed. In 4 of the patients who had villous adenoma and a carcinoma in stage pT1 N0, an R0 resection was performed, resulting in cure of cancer. On the basis of a multivariate regression analysis, the prognosis after oncological resection of cancer of the ampulla is determined by the absence of lymph node metastasis (P<.05), the absence of infiltration into the pancreatic head tissue (P<.05), and the application of an R0 resection. In patients with villous adenoma of the ampulla, ampullectomy was an adequate surgical treatment. In patients with a low-risk cancer in stages pTis and pT1 N0 M0, G1 or G2, a local resection with ampullectomy including local lymph node dissection is justified. An oncological resection of cancer of the ampulla by means of a pylorus-preserving partial pancreatoduodenectomy or the Kausch-Whipple resection is the surgical procedure of choice; the 3- and 5-year survival rates were 72% and 52%, respectively, in patients with R0 resections.