PURPOSE: Microsatellite instability (MSI) is frequently used as an indicative of microsatellite mutator phenotype (MMP) tumors. MSI has been observed in a fraction of non-small cell lung cancer (NSCLC). However, its role in tumorigenesis of NSCLC remains unknown. We evaluated the frequency and pattern of MSI in NSCLC, and compared the clinical parameters of MSI-positive tumors with those of MSS (microsatellite stable) tumors. MATERIALS AND METHODS: Twenty surgically resected NSCLCs were analyzed for 15 microsatellite markers located at chromosome 3p and 9p. Patients' peripheral blood lymphocytes were used as the source of the normal DNA. RESULTS: 1) Of 20 cases, 8 (40%) demonstrated MSI. 2) Instability observed more commonly in tri- and tetra-nucleotide repeats rather than dinucleotide repeats. In all cases, instability appeared as a shift of individual allelic bands. 3) LOH was observed in 10 (50%) of 20 tumors analyzed. 4) Of 20 cases, MSI-H tumor (showing MSI in the majority of markers) was absent. There were 5 MSI-L tumors (showing MSI in a greater than 10% of markers). 5) No significant difference was observed between MSI-L tumors and MSI-negative tumors in clinicopathologic features such as pack-year history of smoking, histologic subtype, and the stage of disease. There was also no significant difference in the incidence of LOH according to the status of MSI. CONCLUSION: These data strongly suggest that MSI has different roles in lung and colon cancer. MMP pathway appears far less important in the tumorigenesis of NSCLC, caused mainly by cigarette smoke, with little familial tendency.