Coronary artery disease (CAD) is a multifactorial disease that results from the interaction between genetic and traditional risk factors. The endothelium dysfunction plays a key role in the progression of atherosclerotic lesions. E-selectin is a marker of endothelium dysfunction. The aim of the present study was to find a relationship between 561A > C and 98G > T polymorphisms of E-selectin gene and CAD as well as interactions between these polymorphic variants and traditional risk factors of the disease in determining the susceptibility to CAD. The study population included 191 patients with angiographically documented CAD and 203 blood donors. The analysis of genetic polymorphisms was performed using the polymerase chain reaction-restriction fragment length polymorphism method. We found that the frequencies of 561C and 98T alleles of E-selectin gene and carriers of C and T alleles were similar in the entire groups as well as in the age-and sex-matched subgroups. We observed a strong significant correlation between those two polymorphisms; almost all subjects possessing one “proatherosclerotic” allele of E-selectin gene also had the second allele (r = 0.963, P < 0.0001). There were also synergistic effects between both polymorphisms and hypercholesterolemia (but not with smoking or overweight) in determining the susceptibility to CAD. The present study points to synergistic interactions between 561A > C or 98G > T polymorphisms of E-selectin gene and hypercholesterolemia that cause a significant increase in the susceptibility to CAD.