Objective To investigate the relationship of the gene polymorphisms of DUSP10 and SMAD7 with colorectal cancer (CRC) susceptivity. Methods For this case-control study we investigated 276 patients with CRC and 385 healthy controls for their peripheral blood sample analysis. SNP was realized with SequenomMassARRAY technology platform. χ2 analysis and SNPStats software were used to analyze the genotype results. We computed the linkage degree with SHEsis software and constructed the haplotypes. Results Based on χ2 test, in the allele model, DUSP10rs908858, SMAD7rs12956924 and rs11874392 were associated with CRC. In the genetic model analyses, under the best model and the Log-additive model, DUSP10rs908858 reduced the risk of CRC while SMAD7rs11874392 increased the risk. Using SHEsis software we found that two blocks in DUSP10L gene were detected. After adjustment by sex and age, we found that haplotype “GTCAA” showed an increased risk of CRC. Conclusion DUSP10 and SMAD7 genes may be associated with CRC in the Xi'an Han population. However, our results need further verification.