Objective-A decreased plasma level of adiponectin is associated with obesity and metabolic syndrome and correlated with endothelial dysfunction. This study aimed to investigate the regulated expression of the newly identified adiponectin receptors (AdipoRl and 2) and their roles in the endothelial expression of intercellular adhesion molecule-1 (ICAM-1) in response to tumor necrosis factor (TNF)-α.Methods and Results-Immunohistochemical study and quantitative RT-PCR demonstrated that globular adiponectin suppressed the TNF-α-induced ICAM-1 expression in a dose-dependent manner in mouse aorta and human umbilical vein endothelial cells (HUVECs). Adenovirus-mediated overexpression of AdipoRl and 2 in ECs significantly enhanced the suppressive effect of a subeffective dose of adiponectin on TNF-α-induced ICAM-1 expression and NF-κB activation. Promoter reporter assays and small interfering RNA revealed that peroxisome proliferator-activated receptor-α may function as an important pathway downstream of adiponectin and its receptors. Furthermore, overexpression of AdipoRs in rat carotid arteries markedly decreased the induction of ICAM-1 in vivo. Conclusions-We provide novel evidence that upregulation of AdipoRs in ECs potentiates the antiinflammatory effect of adiponectin; modulating adiponectin receptors may have potential therapeutic applications for cardiovascular complications associated with metabolic syndrome and diabetes. © 2008 American Heart Association, Inc.