Objectives: K-ras mutation is noted in IPMN as well as in Pancreatic cancer. We investigated K-ras mutation pattern in the pancreatic juice of IPMN in each process of malignant progression. Methods: Between January, 2002 and July, 2007, 51 patients (24 men and 27 women, 68 years old in average) with IPMN were enrolled. DNA was extracted from the cells in pancreatic juice obtained at endoscopic retrograde pancreatography. Point mutations of codon 12 were measured semi-quantitatively by PCR-Preferential Homoduplex Formation Assay. Given that a pattern of K-ras mutation was single, then we defined it as monoclonal pattern. Given that patterns of K-ras mutation were more than two, then we defined polyclonal pattern. We defined the indication of operation arbitrary as following conditions: main pancreatic duct type, or branch type with tumor size over 3 cm in diameter accompanying, either presence of dilated main pancreatic duct over 6 mm in width or presence of mural nodule over 6 mm in height. The IPMN patients were classified into the following 4 groups: carcinoma group (n = 11) and adenoma group (n = 9) both of which were confirmed with histological diagnosis of operation or biopsy, high risk group without operation (n = 5), that were compatible with the criteria of the operation, low risk group (n = 26) that was not compatible with the criteria of the operation. In these four groups, we investigated the incidence of clonal pattern of K-ras mutation by Cochran Armitage test for trend. Results: Mean width of main pancreatic duct were 11 mm in carcinoma group, 7 mm in adenoma group, 4.5 mm in high risk group, 3.3 mm in low risk group. Mean height oh mural nodule were 6 mm in carcinoma group, 4 mm in adenoma group, 0 mm in high risk group, 0 mm in low risk group. The mean observation periods of high risk group and low risk group were 547 days and 687 days, respectively. During this period, IPMN didn't progress malignancy in high risk group. The class 4, 5 of cytology of pancreatic juice were 36% (4/11) in carcinoma group, 0% (0/9) in adenoma group, 0% (0/5) in high risk group, 0% (0/26) in low risk group. The prevalence of K-ras mutation was 81% (9/11) in carcinoma group, 100% (9/9) in adenoma group, 100% (5/5) in high risk group, 73% (19/26) in low risk group. The monoclonal pattern of K-ras mutation were 78% (7/9) in carcinoma group, 67% (6/9) in adenoma group, 40% (2/5) in high risk group, 37% (7/19) in low risk group, the monoclonality of K-ras mutation was significantly correlated in this order. (p = 0.035) Conclusion: It is suggested that the clonal change from polyclonal to monoclonal pattern of K-ras mutation in IPMN is correlated with malignant progression.