Controversies exist regarding the application of the pylorus-preserving pancreatoduodenectomy (PPPD) to malignancies. This study was intended to disclose the pattern of spread of ampullary cancer and to substantiate that tumor spread at resectable stages does not involve the tissues preserved by PPPD. We examined 40 consecutive Whipple pancreatoduodenectomy specimens: mucosal cancer, 4 cases; cancer invading (but not penetrating) the sphincter of Oddi, 1; cancer invading the submucosa of the duodenum, 12; cancer invading the proper muscle of the duodenum, 5; cancer invading the subserosal layer of the duodenum, 7; and cancer invading pancreatic parenchyma, 11. Five cases of mucosal cancer or cancer invading (but not penetrating) the sphincter spread locally without nodal involvement and showed a 5-year survival of 80% without recurrence, being better (p < 0.05) than the 40% survival for patients with more advanced cancers. Sixty-three percent of the remaining 35 cases had metastasis to regional lymph nodes. The 5-year survival of 28% among those with cancer penetrating the proper muscle was worse (p < 0.05) than the 59% survival for those with less advanced cancers. No cases had involved the anatomic structures that would have been preserved by a PPPD. In three cases (7.5%), gastric cancer coexisted. In conclusion, ampullary cancer not penetrating the sphincter spreads locally. Once penetrating the sphincter, it often spreads regionally and causes recurrence. Cancer penetrating the proper muscle of the duodenum bears a worse prognosis. PPPD is an attractive alternative to the Whipple operation for ampullary cancer because no involvement was found in the tissue preserved by the PPPD. However, surgeons should be aware of a concomitant gastric cancer when doing a PPPD.