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Cardiovascular disease is one of the most frequent causes of mortality and morbidity worldwide. Several variables have been identified as risk factors for cardiovascular disease. Recently, the role of receptor activator of nuclear factor kappa B, receptor activator of nuclear factor kappa B ligand, and the osteoprotegerin system has been recognized as more important in the pathogenesis of cardiovascular disease. Besides their roles in the regulation of bone resorption, these molecules have been reported to be associated with the pathophysiology of cardiovascular disease. There are conflicting data regarding the impact of osteoprotegerin, a glycoprotein with a regulatory role in the cardiovascular system. The aim of this review is to discuss the current knowledge and the role of osteoprotegerin in cardiovascular disease.