Cluster of differentiation 1 (CD1) is antigenpresenting molecule involved in the presentation of lipid and glycolipid antigens to specific T cells and natural killer T cells. They exhibit a low rate of polymorphism compared to classical major histocompatibility complex presenting molecules. In this case control study, we examined a possible association of genetic polymorphism in CD1A and CD1D genes with colorectal cancer (CRC) in a Saudi population consisting of 120 patients with CRC and 118 matched controls. They were genotyped for the CD1A T/C 622 and CD1D A/T 354 polymorphisms using PCR-SSP. An apparent protective effect of the C allele, heterozygous TC and additive TC + CC genotypes against CRC was observed. These associations were found only in individuals >57 years. No association was observed between the CD1D A/T 354 polymorphism and CRC.