Human Cripto-1, a membrane-bound protein, plays an important role during early embryogenesis and has oncogenic properties, including cell transformation and enhancement of invasion. Cripto-1 is up-regulated in various malignant tissues and premalignant lesions. However, Cripto-1 expression in intraductal papillary mucinous neoplasms (IPMNs) has yet to be reported. This study aimed to investigate Cripto-1 expression in IPMNs and evaluate the expression patterns according to the histological grade or phenotypic subclassification. Cripto-1 expression was evaluated by immunohistochemistry using 37 IPMN tissue samples and real-time RT-PCR analysis of seven frozen samples. Cripto-1 was up-regulated in 59.5% of IPMNs. Cripto-1 was positively stained in 3 of 4 (75%) adenomas, 12 of 19 (63.2%) borderline neoplasms, 5 of 11 (45.5%) non-invasive carcinomas and 2 of 3 (66.7%) invasive carcinomas. There was no correlation between Cripto-1 overexpression and the histological grade (P>0.05). Cripto-1 expression was significantly increased in pancreatobiliary- (4/5, 80%) and gastric-type (13/19, 68.4.2%) IPMNs compared with those of the intestinal type (2/10, 20%; P<0.01). Cripto-1 mRNA expression was higher in gastric- and pancreatobiliary-type IPMNs than in intestinal ones, supporting the immunohistochemical results. It is concluded that Cripto-1 overexpression is involved in the tumorigenesis of gastric- and pancreatobiliary-type IPMNs.