A total of 304 patients with pancreatoduodenal carcinoma were studied clinicopathologically and immunohistochemically in order to clarify features of carcinoma of four different sites of origin; carcinoma of the ampulla of Vater (Am), the distal common bile duct (DCBD), the head of the pancreas (PH), and the extra-ampullary duodenum (Du). The mean greatest diameter of 87 PH was 3.5 cm compared with 2.7 cm of 149 Am and 2.7 cm of DCBD. Histopathologically, 40% of Am were papillary adenocarcinoma, while about half of DCBD, PH and Du were tubular adenocarcinoma. PH invaded lymphatic (85%), vascular (62%), and perineural (95%) spaces and metastasized lymph nodes (72%) more frequently than Am (77%, 35%, 24%, 50%), DCBD (47%, 61%, 65%, 45%), and Du (76%, 29%, 35%, 65%), respectively. More than 50% of PH invaded the resected margins, whereas in only 2% of Am, the surgical margins were affected by malignant cells. Immunohistochemically, PH was more frequently positive for both carcinoembryonic antigen (CEA) (98%) and carbohydrate antigen (CA) 19-9 (91%) than Am (83%, 62%), DCBD (94%, 58%), and Du (56%, 11%), respectively. The stromal staining type of CEA and CA 19-9 was more frequently seen in PH (27%, 44%) than in Am (9%, 31%), DCBD (11%, 8%) and Du (0%, 0%), showing a more dedifferentiated nature of PH. The cumulative 3-year survival rate of 87 patients with PH (15%) was worse than that of 149 with Am (42%, P less than 0.001), of 51 with DCBD (25%) and of 17 with Du (58%, P less than 0.001). The survival curve of 87 with PH was worse than that of 51 with DCBD, of 149 with Am (P less than 0.001) and of 17 with Du (P less than 0.001). Cox regression analysis, using eleven profound prognostic variables, revealed that venous invasion, perineural infiltration, surgical margin, and histopathologic type were profound prognostic factors. Pancreatic carcinoma has a more dedifferentiated histopathologic nature, showing a more aggressive growth and fares worse than Am, DCBD, and Du.