We immunohistochemically examined material from 36 pancreata (adenocarcinomas, 30 lesions; pancreatic intraepithelial neoplasia [PanIN], 65; normal pancreatic ducts, 30) for cyclooxygenase 2 (COX-2) with an automated platform. We analyzed 7 to 10 discrete foci and generated an average percentage of positive cells and average staining intensity for each lesion. These 2 values were then multiplied to create an overall "HistoScore" for each lesion. COX-2 demonstrated considerable heterogeneity of expression between and within cases. The overall average percentage of positive cells in adenocarcinomas was 47.3%; in PanINs, 36.3%; and in normal ducts, 19.2%. COX-2 was expressed in more than 20% of cells in 23 adenocarcinomas (77%), 42 PanINs (65%), and 12 normal ducts (40%). The overall average HistoScore for adenocarcinomas was 6.1; for PanINs, 5.4; and for normal ducts, 3.5. Significant differences in COX-2 expression were demonstrable in adenocarcinomas vs normal ducts, PanINs vs normal ducts, and PanIN 2/3 vs PanIN 1a/1b. In general, the pattern of COX-2 expression increased from normal to PanIN to adenocarcinoma. The up-regulation of COX-2 in a subset of noninvasive precursor lesions makes it a potential target for chemoprevention with selective COX-2 inhibitors.