Infection with cagA-positive Helicobacter pylori is associated with gastric carcinoma. The cagA-encoded CagA protein is delivered into gastric epithelial cells and, upon tyrosine phosphorylation at the C-terminal EPIYA segments, binds and deregulates SHP-2 oncoprotein. On the basis of the differential alignment of the EPIYA segments, CagA can be subdivided into Western CagA, which is produced by H. pylori isolated in Western countries, and East Asian CagA, which is produced by H. pylori circulating in East Asian countries. Western CagA contains EPIYA-A, EPIYA-B and variable numbers of EPIYA-C segments, whereas East Asian CagA contains EPIYA-A, EPIYA-B and variable numbers of EPIYA-D segments. Upon tyrosine phosphorylation, EPIYA-C and EPIYA-D, respectively, serve as low-affinity and high-affinity SHP-2-binding sites. We previously reported that systemic expression of East Asian CagA (CagA-ABDD) induces gastrointestinal and hematopoietic malignancies in mice. In this study, we generated transgenic mice that systemically express Western CagA (CagA-ABCCC), the levels of which are comparable to those in mice expressing East Asian CagA. The mice developed gastric epithelial hypertrophy and gastrointestinal tumors and also showed lymphoid abnormality but not myeloid abnormalities such as granulocytosis and myeloid leukemia found in mice carrying East Asian CagA. The incidence of tumors in mice expressing Western CagA was significantly lower than that in mice expressing East Asian CagA. Our results indicate that Western CagA is qualitatively less oncogenic than East Asian CagA. Differential oncogenic potential of geographically distinct CagA isoforms may contribute to the differential prevalence of gastric carcinoma between East Asian countries and Western countries.