SMAD7 has been demonstrated to antagonize TGF-β-mediated fibrosis, carcinogenesis, and inflammation. Two previous genome-wide association studies identified three single nucleotide polymorphisms (SNPs) (rs4939827, rs12953717 and rs4464148) in SMAD7 to be associated with colorectal cancer in a Western population. We conducted the first case-control study in a Han Chinese population to explore the associations between these three SNPs and colorectal, gastric, and lung cancers. Of the three SNPs, only rs12953717 was strongly associated with the three types of cancer, fitting the overdominant model. Compared with the CC/TT (CC combined with TT) genotype, the adjusted odds ratios for the CT genotype were 2.002 (95% CI, 1.250-3.207, P = 0.004), 1.678 (95% CI, 1.048-2.689, P = 0.031), 3.825 (95% CI, 2.310-6.335, P < 1 × 10(-4)), and 2.294 (95% CI, 1.537-3.343, P < 1 × 10(-4)), respectively, for colorectal, gastric, lung, and combined cancers. These outcomes suggest that rs12953717 is a common risk marker of these three types of cancer in the Han Chinese.