Based on genome-wide association studies (GWAS) a linkage between several variants such as single nucleotidepolymorphisms (SNPs) in intron 3 of SMAD7 (mothers against decapentaplegic homolog7) were, rs12953717,rs4464148 and rs4939827 has been noted for susceptibility to colorectal cancer (CRC). In this study we investigatedthe relationship of rs12953717 and rs4464148 with risk of CRC among 487 Iranian individuals based on a casecontrolstudy. Genotyping of SNPs was performed by PCR-RFLP and for confirming the outcomes, 10% ofgenotyping cases were sequenced with RFLP. Comparing the case and control group, we have found significantassociation between the rs4464148 SNP and lower risk of CRC. The AG genotype showed decreased risk withand odds ratio of 0.635 (adjusted OR=0.635, 95% CI: 0.417-0.967, p=0.034). There was no significant differencein the distribution of SMAD7 gene rs12953717 TT genotype between two groups of the population evaluated(adjusted OR=1.604, 95% CI: 0.978-2.633, p=0.061). On the other hand, rs12953717 T allele showed a statisticallysignificant association with CRC risk (adjusted OR=1.339, 95% CI: 1.017-1.764, p=0.037). In conclusion, wefound a significant association between CRC risk and the rs4464148 AG genotype. Furthermore, the rs12953717T allele may act as a risk factor. This association may be caused by alternative splicing of pre mRNA. Althoughwe observed a strong association with rs4464148 GG genotype in affected women, we did not detect the sameassociation in CRC male patients.