Background: DNA methyltransferase-3a (DNMT3a) plays significant roles in embryogenesis and the generationof aberrant methylation in carcinogenesis. This study aimed to investigate associations between single nucleotidepolymorphisms (SNPs) of the DNMT3a gene and risk of Helicobacter pylori infection, gastric atrophy and gastriccancer. Methods: The subjects comprised 447 patients with gastric cancer; 111 individuals with gastric atrophyand 961 healthy controls. Two SNPs (rs1550117 and rs13420827) of the DNMT3a gene were genotyped by Taqmanassay. DNMT3a expression was analyzed in cancer tissues from 89 patients by tissue microarray technique. Oddsratio (ORs) and 95% confidence intervals were calculated by multivariate logistic regression. Results: Amonghealthy controls, risk of H.pylori infection was significantly higher in subjects with the rs1550117 AA genotype,compared to those with GG/AG genotypes of DNMT3a [OR=2.08, (95%CI: 1.02-4.32)]. However, no significantcorrelation was found between the two SNPs and risk of developing gastric atrophy or gastric cancer. In addition,no increase in DNMT3a expression was observed in the gastric cancer with H.pylori infection. Conclusions:This study revealed that DNMT3a rs1550117 polymorphism is significantly associated with an increased risk ofH. pylori infection, but did not support any evidence for contributions of DNMT3a rs1550117 and rs13420827to either gastric atrophy or gastric cancer. The biological roles of DNMT3a polymorphisms require furtherinvestigation.