Although remarkable therapeutic advances in the treatment of cardiometabolic disorders have been made with current therapeutic options, cardiovascular disease (CVD) is still a leading cause of mortality and morbidity in the Western world. Therefore, to develop a novel therapeutic strategy is needed for the prevention of cardiovascular disease (CVD) in high-risk patients for atherosclerosis. Recently, we, along with others, have shown that pigment epithelium-derived factor (PEDF), a glycoprotein with potent neuronal differentiating activity, exerts anti-oxidative and anti-inflammatory properties in vascular wall cells, leukocytes and platelets. In addition, PEDF not only suppresses neointimal hyperplasia after balloon angioplasty, but also blocks occlusive thrombus formation in a rat arterial thrombosis model. These observations suggest that substitution of PEDF may be a novel therapeutic strategy for atherosclerosis. This article summarizes the pathophysiological role of PEDF in atherosclerosis and its potential therapeutic implication in this devastating disorder. We also discuss here the kinetics and regulation of PEDF in cardiometabolic disorders in humans.