Adiponectin (APN), an adipocytokine produced by adipose tissue, exerts pleiotropic actions regulating inflammation, metabolism and vascular homeostasis. APN levels are inversely correlated with obesity, type-2 diabetes, hypertension and cardiovascular disease. Although renin angiotensin system (RAS) activation in these interrelated metabolic syndrome components increases angiotensin II (AngII) levels leading to vascular damage, it is unknown whether APN under these conditions provides atheroprotection. We investigated whether increasing plasma APN provides atheroprotection in a hypertensive and accelerated atherosclerosis model. Using adenoviral gene transfer, sustained APN expression increased plasma levels of total and high-molecular weight APN, leading to a significant elevation of plasma HDL-cholesterol (HDL-C). Elevated APN levels were strongly atheroprotective, yet had no impact on blood pressure. Notably, gene expression analyses revealed that APN significantly inhibited the expression of pro-inflammatory and atherogenic genes while it increased the expression of the anti-inflammatory cytokine, IL-10 and the cholesterol efflux transporters, ABCA1 and ABCG1 in the artery wall. These findings suggest that increasing APN levels may be an effective therapeutic strategy to inhibit vascular inflammation and accelerated atherosclerosis associated with RAS activation in the metabolic syndrome.