Background: Dysregulation of the c-MET signaling pathway occurs in a wide range of human cancers including GC. Such derangements result from various molecular mechanisms, including mutations, amplification and overexpression of c-MET. Overexpression and amplification of c-MET have been correlated with poor clinical outcomes in pts with GC. However, the association between c-MET polymorphisms and prognosis in GC is not well defined. We examined the prognostic impact of c-MET polymorphisms on clinical outcomes in pts with localized GC treated with surgery. Methods: One-hundred and sixty-one Japanese pts were included, with localized GC (stage Ib-IV) treated with surgery alone (n=58), or surgery plus adjuvant therapy (n=103) between 2002 and 2010. Median follow up was 4 years. Genomic DNA was extracted from the pts’ blood or tissue. Six functionally significant c-MET SNPs (rs1621, rs40239, rs41736, rs41739, rs184953, rs10234854) were analyzed by PCR-based direct sequencing. All candidate SNPs were analyzed for association with disease free survival (DFS) and overall survival (OS) by uni- and multivariate analyses, adjusting for age, sex, stage and type of adjuvant therapy. Results: The MET rs40239 variant was associated with favorable clinical outcomes. Univariate analysis showed pts with any G (AG/GG) allele had significantly longer DFS and OS compared to those with the AA genotype (HR: 0.43; 95% CI: 0.25-0.74; P=0.001, HR: 0.47; 95% CI: 0.27-0.81; P=0.006, log-rank test, respectively); this remained significant upon multivariate analysis (HR: 0.48; 95% CI: 0.27-0.83; P=0.009, HR: 0.50; 95% CI: 0.28-0.88; P=0.017, respectively). In the subgroup analysis by gender, men, but not women, with the AG/GG genotypes maintained a DFS and OS benefit. Conclusions: Our results show for the first time that the c-MET polymorphism, rs40239, may serve as a prognostic marker in pts with localized GC treated with surgery. There also appears to be a gender-related difference in the impact on clinical outcome by genetic variants of c-MET. Prospective validation of this study is warranted.