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 CA19-9 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 < 0.001), of 51 with DCBD (25%) and of 17 with Du (58%, P < 0.001). The survival curve of 87 with PH was worse than that of 51 with DCBD, of 149 with Am (P < 0.001) and of 17 with Du (P < 0.001). Cox regression analysis, using eleven profound prognostic variables, revealed that venous invasion, perineural infiltration, surgical margin, and histopathologic type were profound pronostic factors. Pancreatic carcinoma has a more dedifferentiated histopathologic nature, showing a more aggressive growth and fares worse than Am, DCBD, and Du.