We conducted a hospital case-control study by genotyping four potential functional single nucleotide polymorphisms (SNPs) to assess the association of Xeroderma pigmentosum complementation group F (XPF) with gastric cancer susceptibility, and role of XPF polymorphisms in combination with H.pylori infection in risk definition. A total of 331 patients with gastric cancer and 355 controls were collected. Four SNPs of XPF, rs180067, rs1799801, rs2276466 and rs744154, were genotyped by Taqman real-time PCR method with a 7900 HT sequence detector system. The gastric cancer patients were more likely to have smoking habit, a family history of cancer and H.pylori infection. We did not find any significant difference in the genotype distributions of XPF rs180067, rs1799801, rs2276466 and rs744154 between cases and controls. However, multivariate logistic analysis showed a non-significant decreased risk in patients carrying rs180067 G allele, rs1799801 T allele or rs2276466 T allele genotypes. A non-significant increased risk of gastric cancer was found in individuals carrying the rs744154 GG genotype. Stratification by H.pylori infection and smoking was not significantly different in polymorphisms of XPF rs180067, rs1799801, rs2276466 and rs744154. The four XPF SNPs did not show significant interaction with H.pylori infection and smoking status (P for interaction was 0.35 and 0.18, respectively). Our study indicated that polymorphisms in rs180067, rs1799801, rs2276466 and rs744154 may affect the risk of gastric cancer but further large sample size studies are needed to validate any association.