This study was undertaken to evaluate the effectiveness of radical lymphadenectomy in ampullary cancer with nodal disease. Thirty-five patients underwent the Whipple procedure with radical lymphadenectomy. The location and number of positive nodes was characterized. Eighteen patients (51%) had positive nodes. Patients without nodal disease (pN0 group) had an actuarial 5-year survival rate of 81%. Seven patients with metastasis confined to the pancreaticoduodenal nodes had a 5-year survival rate of 67%, which was comparable for the pN0 group (N.S.) and better than the 27% 5-year survival rate in patients with positive superior mesenteric nodes (P<0.05). Eleven patients with one to three positive nodes had a 5-year survival rate of 71%, which was also comparable to the pN0 group (N.S.) and better than the 0% 5-year survival rate in patients with four or more positive nodes (P<0.01). Radical lymphadenectomy is effective against a limited degree of nodal disease.