PURPOSE: Colorectal carcinoma (CRC) represents a considerable public health burden in Saudi Arabia. Several candidate genes and genetic variants have been associated with morbidity and mortality among patients with CRC. We explored whether allelic variants of the (rs4646903 and rs1048943), and (rs1042522) genes predisposed nonsmoking Saudi individuals to increased risk for CRC. PATIENTS AND METHODS: DNA from buccal cells of 158 participants (80 with CRC and 78 healthy controls) were analyzed for five SNPs using conventional PCR and TaqMan genotyping assays. The SNPStats software was utilized to choose the best interactive inheritance mode for selected SNPs (https://www.snpstats.net). RESULTS: The mean age of diagnosis was 62.4±13.5 years (range, 40-83 years), with those aged 71-80 years and those aged 40-50 years accounting for the most diagnoses (35.7% and 28.6% of diagnosis, respectively). The and rs1042522 SNPs were associated with CRC (OR= 3.7; < 0.0001, and OR= 1.6; = 0.033, respectively). A plausible contribution to CRC was observed for the and rs1042522 SNPs ( = 14.7; = 0.00013, and = 11.2; = 0.0008, respectively), while the null variant did not affect risk. Heterozygosity in the (rs4646903 and rs1048943 SNPs) was associated with a significant risk for CRC. The / and rs4646903/rs1048943 SNP pairs were in linkage disequilibrium, and the associations were statistically significant (= 0.01 and = 4.6x10, respectively). CONCLUSION: The and rs1042522 variants can increase the development of CRC in Saudi nonsmokers. Even the presence of one copy of a variant allele in the gene can predispose CRC risk. Additional studies should also examine other SNP combinations with lifestyle factors that may help prevent, rather than facilitate, colorectal tumorigenesis.