Background: Biological mechanisms underlying statin and angiotensin II type 1 receptor blocker therapies differ. Therefore, we compared vascular and metabolic responses to these therapies either alone or in combination in hypercholesterolemic, hypertensive patients. 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. Losartan alone or combined therapy significantly reduced blood pressure when compared with simvastatin alone. When compared with losartan alone, simvastatin alone or combined therapy significantly changed lipoproteins. All three treatment arms significantly improved flow-mediated dilator response to hyperemia and decreased plasma MDA and MCP-1 levels relative to baseline measurements. However, these parameters were changed to a greater extent with combined therapy when compared with simvastatin or losartan alone (both P<0.001 and P=0.030 for MCP-1 by ANOVA). Combined therapy or losartan alone significantly increased plasma adiponectin levels and insulin sensitivity (determined by QUICKI) relative to baseline measurements. These changes were significantly greater than in the group treated with simvastatin alone (P<0.001 for adiponectin and P=0.029 for QUICKI by ANOVA). Conclusions: Simvastatin combined with losartan improves endothelial function and reduces inflammatory markers to a greater extent than monotherapy with either drug in hypercholesterolemic, hypertensive patients.