Pancreatic adenocarcinomas are highly invasive cancers for reasons that are currently unclear. Here we sought to determine if the proinvasive integrin alpha6beta4 may be related to pancreatic adenocarcinoma tumor progression. Expression of integrin alpha6beta4 was analyzed via immunohistochemistry for the beta4 subunit in normal pancreas, pancreatic intraepithelial neoplasia (PanIN) lesions, pancreatic adenocarcinomas and chronic pancreatitis. In normal pancreatic ducts, integrin alpha6beta4 was noted only at the cell's basal interface with the basement membrane. In pancreatic adenocarcinomas, 92% (104/113) demonstrated overexpression of integrin alpha6beta4 and altered localization to the cytoplasm and membranous regions. This pattern of expression was observed in all PanIN lesions as early as PanIN-1A, and was evident in lesions that were juxtapositioned to normal epithelium. In contrast, 93% (13/14) of chronic pancreatitis samples resembled the staining pattern of normal pancreas. When cancer was present in areas of chronic pancreatitis, this altered expression of alpha6beta4 integrin identified the cancer. We conclude that integrin alpha6beta4 is expressed only on the basal surface of ductal cells in normal pancreas and chronic pancreatitis. During pancreatic adenocarcinoma progression, the alpha6beta4 integrin is dramatically overexpressed and displays altered localization at the earliest stages of PanIN, thus representing an early event in pancreatic adenocarcinoma progression.