Objective-We tested the hypothesis that carvedilol, a -adrenoceptor and ␣-adrenoceptor antagonist with potent antioxidant property, could inhibit tumor necrosis factor-␣ (TNF-␣)-induced endothelial adhesiveness to human mononuclear cells (MNCs), an early sign of atherogenesis. Methods and Results-Circulating MNCs were isolated from the peripheral blood of healthy subjects. Compared with control condition, pretreatment of carvedilol (10 mol/L for 18 hours) or probucol (5 mol/L for 18 hours), but not propanolol, prazosin, or both propanolol and prazosin significantly decreased TNF-␣-stimulated adhesiveness of cultured human aortic endothelial cells (HAECs) to MNCs. Carvedilol inhibited TNF-␣-stimulated endothelial vascular cell adhesion molecule-1 (VCAM-1) and E-selectin (66.0Ϯ2.0% and 55.60Ϯ1.0% of control, PϽ0.05, respectively) expression, whereas probucol inhibited only VCAM-1 expression (79.0Ϯ5.0% of control, PϽ0.05). Propanolol, prazosin, or both did not alter the expression of adhesion molecules. Further, pretreatment with carvedilol significantly inhibited TNF-␣-stimulated intracellular reactive oxygen species (ROS) production and the activation of redox sensitive nuclear factor kappa B and activator protein-1 transcription pathways. Conclusions-Carvedilol reduced TNF-␣-stimulated endothelial adhesiveness to human MNCs by inhibiting intracellular ROS production, transcription factor activation, and VCAM-1 as well as E-selectin expression, suggesting its potential role in clinical atherosclerosis disease. Key Words: antioxidant Ⅲ atherosclerosis Ⅲ carvedilol Ⅲ cell adhesion molecules Ⅲ endothelium I n the early phase of atherogenesis, cell surface adhesion molecules such as vascular cell adhesion molecule-1 (VCAM-1), intercellular cell adhesion molecule-1 (ICAM-1), and endothelial cell selectin (E-selectin) could express on endothelial cells to recruit circulating mononuclear cells (MNCs), mainly monocytes, and facilitate their binding to endothelium and migrating to subendothelial space. 1-3 Reactive oxygen species (ROS) may serve as a common intracellular messenger for various redox-sensitive transcription pathways that lead to adhesion molecule expression in vascular endothelial cells. 1,4,5 Accumulating in vitro and in vivo evidence showed that substances with antioxidant activity such as probucol and ginkgo biloba extract could scavenge intracellular ROS and inhibit endothelial adhesiveness to monocytes by reducing the expression of various adhesion molecules. 6,7 However, because of the presence of significant side effects or lack of clinical evidence, these drugs are rarely used for human atherosclerosis disease. 8 Carvedilol, 1-[carbazolyl-4-oxy]-3-[(2-methoxyphenoxyethyl)-amino]-propanol-2, a nonselective -adrenoceptor antagonist with ␣1 adrenoceptor blocking and potent antioxidant activity, is currently used for treatment of hypertension or symptomatic heart failure. 9,10 Previous in vitro evidence showed that carvedilol, as an oxidant scavenger, could inhibit cardiomyocyte membrane lipid perox...