Mothers against decapentaplegic homolog 7 (SMAD7) inhibits the transforming growth factor-β (TGF-β) signaling pathway, which regulates carcinogenesis and cancer progression. A number of studies have reported that SMAD7 polymorphisms (rs4464148, rs4939827, and rs12953717) are associated with colorectal cancer (CRC) risk, but the results from these studies remain conflicting. To determine a more precise estimation of the relationship between SMAD7 and CRC, we undertook a large-scale meta-analysis of 63 studies, which included a total of 187,181 subjects (86,585 cases and 100,596 controls). The results of our meta-analysis revealed that the C allele of rs4464148 [CC vs. TT+TC, odds ratio (OR) =1.23, 95% confidence interval (CI): 1.14-1.33, P < 0.01], the T allele of rs4939827 [TT vs. CC+TC, odds ratio OR=1.15, 95%CI:1.07-1.22, P < 0.01] and the T allele of rs12953717 [TT vs. CC+TC, OR =1.22, 95%CI:1.16-1.29, P < 0.01] were all associated with the increased CRC risk. Subgroup analysis according to ethnicity showed rs4464148 and rs12953717 were associated with the risk of CRC in both Caucasians and Asians, whereas rs4939827 was a risk polymorphism for CRC specifically in Caucasians. In summary, this large-scale meta-analysis indicated that SMAD7 polymorphisms (rs4464148, rs4939827, and rs12953717) correlate with CRC.