This is the first study to examine the potential correlation of the rs3796508 and rs5743810 SNPs of the TLR6 gene in patients with colorectal cancer (CRC) in a subset of the Saudi population. TLR6 gene expression was studied by real-time PCR assaysin 10 matching normal and cancer colon tissues. TLR6 expression at the protein level was determined by immunohistochemistry. A case-control search was conductedon 115 case patients and 102 controls. All samples were genotyped with the TaqMan assay for the TLR6 gene. Odds ratios and 95% confidence interval were computed from logistic regression models after adjusting for age, sex, and tumor localization. Our findings showed a decrease in TLR6 expression (p <0.001) in colon cancer tissues when compared to normal colon tissues. Global analysis revealed no significant association between the TLR6 rs3796508 and rs5743810 and CRC in this population. However, the Val/Met genotype of rs3796508 had a significantly higher frequency in the control group than in the cases for the male group (OR= 0.095, and p= 0.03385) or the volunteers aged more than 57 years OR= 0.152; and p= 0.04069, respectively). Two non-synonymous single nucleotide polymorphisms (SNP; S249P and V327M) were common in a few patients and were predicted as damaging by SIFT and Polyphen and were further analyzed for their protein stability and function using advanced bioinformatics tools. The results suggest that TLR6 rs3796508 has a crucial role as a protective factor against colorectal cancer in the older Saudi male population.