Alterations in the p53 tumor suppressor gene are involved in the pathogenesis of diverse human cancers. Immunohistochemical detection of the p53 protein has been strongly correlated with mutations in the p53 gene. Fifty-four human exocrine pancreatic tumors of American, Japanese, and Senegalese origin and six xenotransplanted human pancreatic carcinoma cell lines were investigated immunohistochemically with monoclonal anti-p53 antibodies pAb 1801 and BP53-12. Positive nuclear p53 immunoreactivity was detected in 37% of paraffin-embedded primary tumors (21.8% in the Japanese group, 52.6% in the American group) and in 50% of xenotransplanted carcinoma cell lines. Since several intraductal papillary adenocarcinomas exhibited positive p53 immunostain, it seems probable that alterations in this tumor suppressor gene occur relatively early in the process of pancreatic carcinogenesis. No clear correlation was established between p53-positive immunohistochemical staining and tumor stage and histologic appearance, nor with patient age, sex, or survival time. In contrast to ductal carcinomas and intraductal papillary adenocarcinomas, none of the mucinous or adenosquamous pancreatic carcinomas exhibited positive nuclear staining for p53. The fact that more than half of the ethanol-fixed fine-needle aspirates were positive for p53 suggests that this type of immunostain may be of potential diagnostic significance. An investigation of a large series of pancreatic tumors is needed to further evaluate the relationship between p53 alterations and clinicopathologic features in human pancreatic cancer.