To investigate whether DNA directly induces gastritis and/or peptic ulcer, we injected synthetic DNA including CpG motif (CpG-DNA) to mouse stomach. BALB/c mice were injected with either saline, acetic acid (AA), CpG-DNA, or Control-DNA. Mice were sacrificed, and sections of the stomachs were stained with hematoxylin and eosin. The lesions were histopathologically scored from 0 to 4 based on the extent of the inflammation. Populations of neutrophils and mononuclear cells infiltrated to the lesion were calculated. IFN-y mRNA expression at the injection site was analyzed by RT-PCR. The number of CpG motifs included in the complete genomes of H. pylori HP26695 and J99, Escherichia coli O157, and Salmonella Typhi was determined by genomic analysis of these bacteria. Intragastric injection with CpG-DNA induced gastritis, and statistical analysis of histological scores revealed a significant difference between saline vs CpG-DNA (p = 0.037). The population of mononuclear cells infiltrated to the lesions was significantly higher in mice injected with CpG-DNA than that injected with AA (p = 0.0061). IFN-gamma mRNA expression was detected in the CpG-DNA group. While H. pylori includes multiple CpG motifs in its genome, it has fewer than the other pathogenic gram-negative bacilli. We conclude that synthetic DNA including CpG motif directly causes gastritis in mice and induces IFN-gamma production in the stomach. Bacterial DNA including CpG motif is known to stimulate innate immunity and to cause inflammation. Thus, H. pylori genomic DNA may be one of the virulent factors involved in H. pylori infection.