Background: Three recent genome-wide association studies (GWASs) have reported that three SNPs (rs4072037, rs13361707 and rs2274223) located on genes related to host inflammatory response are significantly associated with susceptibility to gastric cancer (GC) in Chinese populations. Helicobacter pylori infection is also an important risk factor for GC through causing inflammatory response in the gastric mucosa. However, no study has established whether there are potential gene-environment interactions between these genetic variants and H. pylori infection to the risk of GC. Methods: We genotyped three polymorphisms (rs4072037 at 1q22, rs13361707 at 5p13, and rs2274223 at 10q23) in 335 Chinese gastric adenocarcinoma patients and 334 controls. H. pylori serology was examined by enzyme-linked immunosorbent assay. Multivariable logistic regression models were used to evaluate the association between the variables and GC risk. Results: We confirmed that the three SNPs (rs4072037, rs13361707 and rs2274223) were significantly associated with GC susceptibility. H. pylori infection also significantly increased the risk of GC. Furthermore, there were joint effects between H. pylori infection and the three SNPs on the risk of GC. The most elevated risk of GC was found in subjects with H. pylori seropositivity and AA genotypes for rs4072037 [ odds ratio (OR), 3.95; 95% confidence interval (CI), 2.29-6.79], H. pylori seropositivity and CT/CC genotypes for rs13361707 (OR, 2.68; 95% CI, 1.62-4.43), H. pylori seropositivity and AG/GG genotypes for rs2274223 (OR, 2.45; 95% CI, 1.55-3.88) compared with those with H. pylori seronegativity and other genotypes of each SNP. Significant interactions were observed between H. pylori seropositivity and the three SNPs (all P-Gx (E) < 0.05) to the risk of GC. Conclusion: These findings indicate that the three SNPs (rs4072037, rs13361707 and rs2274223) identified in the GWASs may interact with H. pylori infection to increase the risk of GC.