Background: Biological mechanisms underlying statin and fibrate therapies differ. Therefore, we compared vascular and metabolic responses (as well as adverse responses) to these therapies either alone or in combination in patients with combined hyperlipidemia. Methods: 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). Fifty-six patients were given atorvastatin 10 mg and placebo, atorvastatin 10 mg and micronized fenofibrate 200 mg, or micronized fenofibrate 200 mg and placebo daily during each 2 month treatment period. Results: Lipoproteins were changed to a greater extent with combined therapy when compared with atorvastatin or fenofibrate alone. Flow-mediated dilator response to hyperemia and plasma hsCRP and fibrinogen levels were changed to a greater extent with combined therapy when compared with atorvastatin or fenofibrate alone (P<0.001, P=0.182, and P=0.015 by ANOVA, respectively). The effects of combined therapy or fenofibrate alone on plasma adiponectin levels and insulin sensitivity (determined by QUICKI) were significantly greater than those of atorvastatin alone (P=0.022 for adiponectin and P=0.049 for QUICKI by ANOVA). Following combined therapy, improvement in flow-mediated dilation correlated with changes in total cholesterol levels (r=-0.373 and p=0.005), triglycerides levels (r=-0.288 and p=0.032), and apolipoprotein B levels (r=-0.341, p=0.010). There were significant correlations between percent changes in adiponectin levels and percent changes in QUICKI (r=0.283, p=0.034), apolipoprotein A-I (r=0.351, p=0.008) and insulin (r=-0.332, p=0.013) after combined therapy. No patients were withdrawn due to serious adverse effects. Conclusions: Combination therapy is safe and has beneficial additive effects on endothelial function in patients with combined hyperlipidemia.