In the Saudi population, colorectal cancer (CRC) is the first and third most common malignancy among males and females, respectively. The CRC risk is associated with the expression of certain genes, which can be used for prognoses and for finding screening-related biomarkers. One such gene is melanoma-associated antigen 1 (MAGE-A1); however, little is known about this gene or its expression as it relates to CRC susceptibility in Saudi patients. The aim of this study was to use the TaqMan genotyping assay to explore the relationship between MAGE-A1 single nucleotide polymorphisms (SNPs), specifically rs3788745, rs3788749, and rs3788753, and CRC susceptibility in 192 Saudi patients with CRC and 192 healthy individuals (a control group). The rs3788749 SNP exhibited an increased prevalence in individuals with the CT and CT + TT genotypes, indicating a correlation between the presence of MAGE-A1 polymorphism and susceptibility to CRC (p=0.038 and 0.026, respectively). The CRC group also showed a significant difference in allele frequency (T alleles) when compared to the control group (p=0.019). Categorizing the patients with CRC by tumor location revealed a high prevalence of MAGE-A1 rs3788749 polymorphism in patients with rectal localizations and the CT and CT + TT genotypes (p=0.014) and the T alleles (p=0.023). However, no significant differences were found in the clinical and demographic parameters related to MAGE-A1 SNPs rs3788745 and rs3788753 in terms of the genotype and allele frequencies in patients with CRC when compared to healthy individuals. In conclusion, MAGE-A1 rs3788749 polymorphism is associated with an increased susceptibility to CRC, and especially rectal cancer, suggesting that this polymorphism may serve as a rectal cancer biomarker for the early detection of CRC in Saudi patients.