Growing evidence suggests that the transforming growth factor β (TGF-β) signaling pathway occupies a central position in the signaling networks that control cell growth and differentiation. TGF-β1 and its receptor TGF-βRII have been correlated with the development of certain forms of cancer, including gastric cancer. We hypothesized that functional genetic variants in TGFB1 and TGFBR2 are associated with gastric cancer risk. To test this hypothesis, we genotyped C-509T and Leu10Pro polymorphisms in TGFB1 and G-875A variant in TGFBR2, using the primer-introduced restriction analysis (PIRA)-PCR assay, in a case–control study of 675 gastric cancer cases and 704 healthy controls in a Chinese population. We found that the variant alleles of the promoter polymorphisms, TGFB1 C-509T and TGFBR2 G-875A, were associated with a significantly decreased risk of gastriccancer [adjusted odds ratio (OR) = 0.65, 95% confidence interval (CI) = 0.52–0.82 for −509CT/TT and adjusted OR = 0.67, 95% CI = 0.53–0.85 for −875GA/AA]. Furthermore, subjects with both variant genotypes of the TGFB1 C-509T and TGFBR2 G-875A were associated with a significantly (56%) decreased risk of gastric cancer (adjusted OR = 0.44, 95% CI = 0.32–0.62). These findings indicate, for the first-time, that the functional variants in the promoter of TGFB1 and TGFBR2 might contribute to gastric cancer susceptibility. © 2006 Wiley-Liss, Inc.