Several known functions of high-density lipoproteins (HDLs) may contribute to their ability to protect against atherosclerosis. The best known of these functions is the ability to promote cholesterol efflux from cells in a process that may minimize the accumulation of foam cells in the artery wall. However, HDLs have additional properties, including antioxidant, antiinflammatory, and antithrombotic effects, that may also be anti-atherogenic. Recent in vivo studies in several animal models have demonstrated that HDLs can inhibit acute and chronic vascular inflammation. The fact that these effects can be achieved with very low doses of reconstituted discoidal HDL or even lipid-free apolipoprotein A-I suggests that they may reflect activity of a minor, highly active HDL subpopulation. These results have potentially important clinical implications in regard to managing the acute vascular inflammation states that accompany acute coronary sydrome and acute ischemic stroke.