Coronary artery disease (CAD) and type 2 diabetes mellitus (T2DM) are important and increasing public health problems. This study aimed to identify the impact of APOE and CLU gene polymorphisms on the prevalence of both diseases, along with the effect of these polymorphisms on lipid profile and glucose metabolism.736 CAD patients (≥50 stenosis) and 549 non-CAD subjects (≤30 stenosis) were genotyped for APOE (rs429358 and rs7412) and CLU (rs11136000) gene polymorphisms using hydrolysis probes in real-time PCR. Blood samples of the individuals were drawn before coronary angiography and biochemical analyses were done. The associations between the polymorphisms and the selected parameters were assessed using statistical analysis.In this study, the ε2 and ε4 isoforms of apoE were associated with serum lipid levels and TC/HDL-C and LDL-C/HDL-C ratios in analysis adjusted for several confounders and in crude analysis. It was observed that CLU T allele carrier non-CAD subjects had lower glycosylated hemoglobin levels. Furthermore, the effects of APOE and CLU polymorphisms were assessed on CAD and T2DM presence. In crude and multiple logistic regression analyses, the ε2 isoform carriers had a lower risk for CAD complexed with T2DM. When the combinational effects of APOE and CLU polymorphisms were examined, the ε2 and T allele carriers had decreased risk for CAD complexed with T2DM compared to non-carriers.In conclusion, the combination of APOE and CLU polymorphisms is associated with CAD-DM status along with the APOE ε2 isoform by itself, and the apoE isoforms are strongly associated with serum lipid levels.