Background: The proinflammatory mediator CD40 ligand plays an important role in atherogenesis. Biological mechanisms underlying statin and angiotensin II type 1 receptor blocker therapies differ. Therefore, we compared the effects of these therapies either alone or in combination on plasma soluble CD40 ligand (sCD40L). Methods and Results: This was a randomized, double-blind, placebo-controlled cross-over trial with three treatment arms (each 2 months) and two washout periods (each 2 months). Forty-seven hypertensive, hypercholesterolemic patients were given simvastatin 20 mg and placebo, simvastatin 20 mg and losartan 100 mg, or losartan 100 mg and placebo daily during each 2 month treatment period. Simvastatin alone did not significantly reduce sCD40L levels relative to baseline measurements, however, simvastatin significantly reduced sCD40L levels from 4.25짹0.33 to 2.84짹0.33 ng/mL (P=0.004) in patients with high baseline sCD40L >2.0 ng/mL. Combined therapy or losartan alone significantly decreased the plasma sCD40L levels relative to baseline measurements by 14짹7% (P=0.001) and 13짹10% (P=0.001), respectively. These decreases were significantly greater than those observed with simvastatin alone (P=0.023 by ANOVA). Of interest, there were significant inverse correlations between baseline sCD40L levels and percent changes in sCD40L levels (r=-0.456, P=0.001 after simvastatin alone; r=-0.476, P<0.001 after combined therapy; r=-0.451, P=0.002 after losartan alone, respectively). Conclusions: Losartan alone and combined therapy significantly reduced plasma sCD40L levels more than simvastatin alone in hypercholesterolemic, hypertensive patients. Simvastatin, losartan and combined therapy significantly reduced sCD40L to the greatest extent in patients with high baseline sCD40L levels.