Introduction:The CUB and Sushi multiple domains 2 gene (CSMD2) is a member of CSMD gene family, located on chromosome 1p34.3, consists of 70 exons. The CSMD2 gene mutation has been found in pancreatic, colorectal and small cell lung cancers, suggesting that CSMD2 may be a tumor suppressor gene. Here, we investigated the association of CSMD2 polymorphisms with cancer.Methods:Genotyping was performed in 2,343 consecutive autopsy cases enrolled in the JG-SNP database via Illumina Infinium human Exome BeadChip array. Presence of cancer, including occult cancer was investigated by pathologists. Association of SNVs and cancer was analyzed by logistic regression analysis. Results:A total of 110 CSMD2 SNVs were genotyped and 26 SNVs were polymorphic. SNVs, rs474474 (H538R), rs199962081 (L855F), rs2641962 (M2554V), rs376790279 (R2096K), rs580682 (silent) had significant association with cancers in general (p=0.002), pancreas (p=0.001), colorectal (p=0.012), prostate (p=0.026, 0.043), lung (p=0.008) and liver (p=0.027), respectively. Discussion:CSMD2 gene polymorphism rs474474 (H538R) was protective to total cancer. Other CSMD2 gene polymorphisms demonstrated associations with different types of cancer. CSMD2 gene polymorphisms warrant further investigation in larger sample size cohorts, and their potential functional consequences need to be clarified.