Abstract: Objective To investigate the relationship between single nucleotide polymorphism(SNP), rs689466, rs5275, rs4648308, in COX-2 gene and the risk of non-cardia gastric cancer. Methods Three tested SNPs were genotyped by TaqMan method among 288 patients with non-cardia gastric cancer and 281 normal controls. Haplotype was constructed by Haploview software. Odds ratio(OR) and 95% confidence intervals (95%CI) were measured by Logistic regression analysis to evaluate the correlations of the alleles, genotypes, and haplotypes with the susceptibility to non-cardia gastric cancer. Results SNP rs5275 C allele and rs4648308 A allele were significantly associated with an increased risk of non-cardia gastric cancer. And rs5275 CT, CC genotypes and rs4648308 GA genotype were also significantly associated with an increased risk of non-cardia gastric cancer (rs5275: CT vs. TT: OR=1.458, 95% CI: 1.015-2.096); CC vs. TT: OR=3.704, 95%CI: 1.184-11.59; rs4648308: GA vs. GG: OR=3.387, 95%CI:1.953-5.872). Furthermore, haplotype ACA was significantly associated with a higher risk of non-cardia gastric cancer, compared with GTG haplotype (OR=3.198, 95%CI: 1.854-5.516). Conclusion SNP rs5275 and rs4648308 in COX-2 gene are associated with the risk of non-cardia gastric cancer.