BACKGROUND: We hypothesized that atorvastatin combined with amlodipine has additive beneficial vascular and metabolic effects that are superior to monotherapy in patients with hypertension. METHODS: Forty-two patients were given atorvastatin 20mg/day and placebo, atorvastatin 20mg/day and amlodipine 10mg/day, or amlodipine 10mg/day and placebo during each 2-month treatment period of a randomized, single-blind, placebo-controlled cross-over trial with two 2-month washout periods. RESULTS: Atorvastatin combined with amlodipine or amlodipine alone significantly reduced blood pressure to a greater extent than atorvastatin alone (all P<0.001 by ANOVA). Atorvastatin combined with amlodipine significantly reduced plasma malondialdehyde and improved flow-mediated dilation to a greater extent than atorvastatin or amlodipine alone (all P<0.001 by ANOVA). Atorvastatin therapy significantly increased insulin levels (P=0.004) and decreased plasma adiponectin levels (P=0.016) and insulin sensitivity (determined by QUICKI; P=0.026) relative to baseline measurements. Amlodipine therapy significantly decreased insulin levels (P=0.001) and increased adiponectin levels (P<0.001) and insulin sensitivity (P=0.003) relative to baseline measurements. Atorvastatin combined with amlodipine therapy significantly increased adiponectin levels (P<0.001) and insulin sensitivity (P=0.034) relative to baseline measurements. Effects of all three therapeutic arms on adiponectin levels and insulin sensitivity were statistically significant (P<0.001 by ANOVA). CONCLUSIONS: Atorvastatin combined with amlodipine therapy improves endothelial function and increases adiponectin levels and insulin sensitivity to a greater extent than monotherapy with either drug in hypertensive patients.