1. CD40 and CD40 ligand (CD40L) have a critical role in the pathophysiology and risk prediction of coronary artery syndrome, including atherothrombosis and atherosclerosis. However, the contribution of the CD40/CD40L dyad, especially the soluble form of CD40L (sCD40L), to the pathophysiology of hypertension and associated organ damage remains unknown. 2. In the present study, serum levels of CD40 and sCD40L were measured in 328 hypertensive patients with varying degrees of organ damage. The data revealed that serum levels of CD40 were significantly greater in patients with severe, but not mild, organ damage compared with patients without any organ damage. There were no significant differences in serum concentrations of sCD40L between patients with no, mild and severe organ damage. Concentrations of soluble CD40 were comparable in patients with mild organ damage that included left ventricular hypertrophy, retinal damage, renal dysfunction and proteinuria. In contrast, concentrations of soluble CD40 were increased significantly in patients with certain forms of severe organ damage, specifically stroke, but not coronary and peripheral artery disease. 3. Collectively, our data indicate that upregulation of the CD40 system in hypertensive patients with certain forms of severe end-organ damage may contribute to the pro-inflammatory, pro-atherogenic and prothrombotic milieu in hypertension.