From epidemiological evidence a high salt diet is a risk factor for gastric cancer, independent of Helicobacter pylori infection, and animal studies have shown that salt promotes carcinogenesis. The G-protein β 3(GNB3) C825T polymorphism has been linked with hypertension, salt sensitivity and multiple diseases. Our aim in this study was to clarify any association of the GNB3 C825T polymorphism with gastric cancer risk in Japanese. We examined 161 patients with gastric cancer and 183 control subjects. All underwent stomach biopsy by endoscopic procedures, and extracted DNA was genotyped using a primer pair including the GNB3 C825T polymorphism area by PCR-based restriction fragment length polymorphism (PCR-RFLP). Logistic-regression analysis was performed to assess the impact of the genetic polymorphism. Overall comparison of genotype frequency showed the CT genotype in control patients to be relatively infrequent, but no statistically significant differences were found. However, on comparison of subtypes of gastric cancer (intestinal and diffuse), a significantly increased risk of diffuse type of gastric cancer was foudn for the TT genotype (odds ratio compared to CC, 3.1, 95%CI 1.1-8.6, p=0.03). In conclusion, the TT genotype of GNB3 was associated with diffuse type of gastric cancer. The mechanism of the GNB3 polymorphism interaction with gastric cancer development needs to be clarified by future study.