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Abstract. Aims:. Catechol-O-methyltransferase (COMT) plays a role in many kinds of cancer, and its high expression in pancreatic cancer has been found to be related to better prognosis. However, the expression and biological significance of COMT in multistep pancreatic cancerogenesis is not clear. Main methods:. Six LSL-KrasG12D-positive and Pdx1-Cre-positive mice (KrasG12D mice), 6 wild-type mice and 1 human tissue microarray were used in this study. COMT protein expression was measured by immunohistochemistry, and DNA chips were made for use in COMT mRNA assays. Key findings:. The expression of COMT in pancreatic intraepithelial neoplasias (PanINs) from KrasG12D mice was significantly higher than that in normal pancreatic tissue from wild-type mice, both in terms of protein level and mRNA expression. The median COMT immunohistochemistry expression scores in human PanIN-1 and PanIN-2 were 70 and 160, respectively, which were significantly lower than the score of 170 observed in pancreatic ductal adenocarcinoma (PDAC) (P = .024 and .037, respectively) and significantly higher than the score of 25 observed in pancreatitis (P = .01 and .008, respectively). Significance:. In the development of pancreatic cancer from chronic pancreatitis and in the transition of PanIN to PDAC, we observed significantly increased expression of COMT. These data predict that the overexpression of COMT is an early event in the multistep process of pancreatic cancerogenesis.