DeltaNp63 (DNp63) has become widely used, in particular, for distinguishing invasive carcinomas from noninvasive ducts by highlighting the myoepithelial or basal cells in the breast and prostate, respectively. It is not known whether this marker may have any application in another exocrine organ, the pancreas. As the ductal and intraductal proliferations of this organ become better characterized, the need for markers to distinguish among these processes increases. We investigated immunohistochemical expression of DNP63 in 105 cases. A total of 25 cases were non-neoplastic pancreata, 25 were pancreatic intraepithelial neoplasia (PanIN) of various grades, and 50 were examples of pancreatic ductal adenocarcinoma. Sections of non-neoplastic pancreata included various types of non-neoplastic processes such as squamous/transitional metaplasia (five cases), which can be mistaken for high-grade PanINs, as well as various degrees of reactive ductal atypia and incidental microcysts with attenuated lining (five cases). No DNp63 expression was noted in normal pancreatic ducts. On the other hand, all five foci of squamous/transitional metaplasia were strongly and uniformly positive for this marker. DNp63 labeling was also noted in those incidental microcysts lined by attenuated cells, seen amidst normal pancreatic lobules. All PanINs were negative. Among invasive carcinomas, DNp63 expression was detected only in areas of squamous differentiation and was completely absent in ordinary ductal areas. Based on this observation, five additional cases of adenosquamous/squamous carcinoma was retrieved and stained, and the squamous components of all of these were also positive. In conclusion, (I) DNp63 is a reliable marker of squamous differentiation in the pancreas. It is valuable in distinguishing squamous/transitional metaplasia from PanINs, a distinction of importance for both researchers and diagnosticians. Among invasive carcinomas, it seems to be entirely specific for areas of squamous differentiation. (II) Those incidental microcysts seen in acinar lobules and lined by attenuated cells are also positive for DNp63, which suggests that they may be metaplastic in nature, and that they do not represent neoplastic cells. (III) Unlike the ducts of other exocrine organs, breast and prostate, there are no DNp63-expressing cells in the normal pancreatic ducts, and therefore, this marker cannot be used in distinguishing invasive carcinomas from the non-invasive ducts. (IV) No p63-expressing 'stem' cells are present in the pancreas.