In a prospective observational study including 34 patients with carcinoma of the ampulla of Vater, postoperative morbidity, mortality, and long-term survival were analyzed to determine the surgical procedure of choice. Surgically related postoperative complications were observed in 35.4% of patients after pancreatic resection. No patient died within the first 30 days postoperatively, and in-hospital mortality was 3%. Lymph node metastases were associated only with moderate or undifferentiated tumors larger than 0.6 cm in diameter that infiltrated beyond the ampulla of Vater. The median follow-up time was 4.3 years. The 5-year survival rate for the 31 patients undergoing radical resection was 62.7%. Multivariate analysis (including the covariates depth of tumor infiltration, lymph node metastases, and the ratio of metastatic to dissected lymph nodes) demonstrated that only this ratio exerted an independent influence on the prognosis (p = 0.001). The present series demonstrates that radical resection of ampullary cancer is the procedure of choice even in elderly patients. The most important factor influencing the survival rate is the extent of the lymph node dissection. The histopathologic investigation of our pancreatoduodenectomy specimens demonstrates clearly that local excision of ampullary cancer may be indicated only in high risk patients with a pT1, well differentiated tumor smaller than 0.6 cm in diameter.