The transforming growth factor (TGF)-β is a potent growth inhibitor primarily responsible for cell growth, differentiation, and apoptosis, and frequently perturbed during development of tumors, including gastric cancer. TGF-β receptor type I (TGFβR1) may be a modifier of cancer risk by constitutively decreasing the TGF-β inhibitory signals during early tumorigenesis and increasing the TGF-β signals in tumor progression. In this study, we hypothesized that genetic variants of TGFBR1 may influence the risk of gastric cancer. We conducted a two-stage case–control study of gastric cancer, including 650 cases and 683 controls in the first stage and 484 cases and 348 controls in the second stage, and genotyped five tagging single nucleotide polymorphisms (SNPs) to represent common variants in the whole TGFBR1 gene. In the first stage, two SNPs rs6478974 and rs10512263 were found to be potentially associated with risk of gastric cancer (P = 3.35 × 10−3 for rs6478974 AT vs. TT and P = 0.033 for rs10512263 CT vs. TT), which were further confirmed in the second stage with similar effects (P = 0.144 and 0.049, respectively). After combining the two stages, we found that these two SNPs were associated with a significantly increased risk of gastric cancer in dominant models [adjusted odds ratio (OR) = 1.36, 95% confidence interval (CI): 1.14–1.63 for rs6478974 AT/AA vs. TT; adjusted OR = 1.26, 95% CI: 1.05–1.50 for rs10512263 CT/CC vs. TT] or additive model (adjusted OR = 1.23, 95% CI: 1.08–1.40 for rs6478974). These findings indicate that TGFBR1 polymorphisms may be implicated with the development of gastric cancer in Han-Chinese population. © 2012 Wiley Periodicals, Inc.