Despite the benefit of statins in reducing cardiovascular risk， a sizable proportion of patients still remain at risk. Since HDL reduces CVD risk through a process that involves formation of pre-beta particles that facilitates the removal of cholesterol from the lipid-laden macrophages in the arteries， inducing pre-beta particles， may reduce the risk of CVD. A novel BET bromodomain antagonist， RVX-208， was reported to raise apoA-I and increase preβ-HDL particles in non-human primates and humans. In the present study， we investigated the effect of RVX-208 on aortic lesion formation in hyperlipidemic apoE(-/-) mice. Oral treatments of apoE(-/-) mice with 150?mg/kg b.i.d RVX-208 for 12 weeks significantly reduced aortic lesion formation， accompanied by 2-fold increases in the levels of circulating HDL-C， and ～50% decreases in LDL-C， although no significant changes in plasma apoA-I were observed. Circulating adhesion molecules as well as cytokines also showed significant reduction. Haptoglobin， a proinflammatory protein， known to bind with HDL/apoA-I， decreased >2.5-fold in the RVX-208 treated group. With a therapeutic dosing regimen in which mice were fed Western diet for 10 weeks to develop lesions followed by switching to a low fat diet and concurrent treatment with RVX-208 for 14 weeks， RVX-208 similarly reduced lesion formation by 39% in the whole aorta without significant changes in the plasma lipid parameters. RVX-208 significantly reduced the proinflammatory cytokines IP-10， MIP1(?) and MDC. These results show that the antiatherogenic activity of BET inhibitor， RVX-208， occurs via a combination of lipid changes and anti-inflammatory activities.