The purpose of this study was to clarify the prognostic significance of transfusion following pancreatoduodenectomy for periampullary cancers. We analyzed 357 periampullary cancers from 1985 to 1997 (ampullary cancer 130 cases, distal bile duct cancer 141 cases, pancreatic head cancer 86 cases). A total of 215 (60%) of the 357 patients have received intraoperative transfusion. The 5-year survival rate of 130 ampullary cancer patients was 59%; altogether, 76 patients (58%) underwent intraoperative transfusion. The 5-year survival rate of patients without intraoperative transfusion was 79%, whereas that of patients with a transfusion was 47% (p = 0.029). Following multivariate analysis, intraoperative transfusion was found to be an independent poor prognostic factor for those with ampullary cancer (relative risk 2.174). Among those with common bile duct cancer, the overall 5-year survival rate was 33%, and the 5-year survival rates for patients with (n = 87) or without (n = 54) transfusion were 25% and 38%, respectively, which did not reach statistical significance (p = 0.0717). For those with pancreatic head cancer, the overall 5-year survival rate was 16%, and there was no survival difference between transfused (n = 52) and untransfused (n = 34) patients. In the present study the reason was not clear, although intraoperative transfusion was an independent significant prognostic factor for ampullary cancer. Careful dissection to minimize intraoperative bleeding is mandatory during pancreatoduodenectomy for ampullary cancer.