Caveolin-1 (CAV-1) plays a crucial role in endothelial-nitric oxide synthase (eNOS) enzymatic activity. Therefore, CAV-1 and eNOS interactions have a significant impact on endothelial dysfunction, cholesterol levels, and atherosclerosis. We investigated the critical variations in NOS3 and CAV1 genes in this case-control study to determine the relations between the coronary heart disease (CHD) risk factors. The NOS3-rs1799983, CAV-1 rs3840634, and rs3807990 variations were analyzed in 76 CHD patients and 91 controls using the polymerase chain reaction. Mean serum Total-cholesterol levels were significantly higher in CHD patients with the CAV-1 rs3807990-T allele than in patients with CC genotype (p=0.017). There was a statistically significant correlation between the rs3807990-T allele and hypercholesterolemia in the CHD group (p=0.008). The multivariate analysis confirmed that the CAV-1 rs3807990-T allele (p=0.011) is a risk factor for hypercholesterolemia. Moreover, the serum HDL-Cholesterol level was detected to be higher in patients carrying both CAV1-rs3807990-T and NOS3-rs1799983-T alleles than those with the CAV-1 rs3807990-CC/NOS3-rs1799983-GG genotype subgroup (p=0.013). These results suggested that the genetic variations of CAV-1 rs3807990 and NOS3-rs1799983 may contribute to the increased hypercholesterolemia risk and thus on the development of CHD.