Given the recent findings on the importance of CD38 signaling in the pathogenesis of colon cancer. We hypothesized that single nucleotide polymorphisms (SNP) in the CD38 gene may be related to colon cancer risk. CD38 has a genetic polymorphism, characterized by a C>G variation in the regulatory region of intron 1. The working hypothesis is that the presence of different alleles in colon cancer patients accounts for some of the clinical heterogeneity. CD38 is considered a marker of prognosis and as an indicator the activation and proliferation of cells. We hypothesized that single nucleotide polymorphisms (SNP) in the CD38 gene may be related to colon cancer risk. We evaluated one potentially functional CD38 SNP, intronic rs6449182 in two cases patients and controls. Genotyping was done using PCR-based assays in a total of 93 patients with colon cancer and 100 controls. We found that frequencies of variant allele (rs6449182 G) were significantly higher in colon cancer. Logistic regression analysis revealed an association between colon cancer and genotypes: rs6449182 CC [odds ratio (OR), 0.57; 95% confidence interval (95% CI), 0.32 – 1.01], rs6449182 CG (OR, 1.47; 95% CI, 0.83 – 2.60), and rs6449182 GG (OR, 2.26; 95% CI, 0.66 – 7.77). We observed that rs6449182 G carriers had more advanced clinical stage (P = 0.04). In conclusion, our data show that CD38 SNP may affect CD38 expression and contribute to the increased risk of colon cancer carcinogenesis.