Abstract: Background and Objective: Colorectal cancer (CRC) is one of the most common cancers worldwide. In 2018, CRC was considered the 3rd deadliest cancer globally. Several risk factors are associated with CRC carcinogenesis such as lipid metabolism alterations. Apolipoprotein is a key regulator in lipid metabolism as it controls cholesterol and triglyceride levels and facilitates the clearance of cholesterol and low-density lipoprotein (LDL) cholesterol from plasma. In this study, (apoE HhaI) genotypes were investigated in Saudi CRC patients to evaluate the contribution of these genotypes to CRC carcinogenesis. Materials and Methods: This case-control study included 66 CRC patients and 65 controls. The gDNA samples were collected from blood and then different apoE genotypes were determined by PCR-RFLP assay. Results: The four genotypes were distributed in CRC patients (E2/E3, E3/E3, E3/E4 and E4/E4), whereas, in controls, only two genotypes were determined (E2/E3 and E4/E4). However, none of the genotypes of the apoE gene were correlated with CRC risk (p>0.05). Interestingly, the E2/E3 and E4/E4 genotypes were the most distributed apoE genotypes in high grade CRC patients. Conclusion: Data from the current study might shed light on the correlation of apoE genotypes with CRC progression. However, more studies are required to reveal the molecular mechanisms that affect lipid metabolism.