Apolipoprotein (apo) A-I, because of its anti-atherogenic properties, provides a potentially powerful approach to the management of vascular diseases. In the clinic, patients with low high density lipoproteins (HDL)/apoA-I are at dramatically increased risk of coronary disease, the opposite being true for individuals with high HDL Drug studies, e.g., the VA-HIT trial with gemfibrozil, clearly associated a reduced risk of events with raised HDL-cholesterolemia. A number of animal studies have shown that the infusion of apoA-I containing synthetic HDL can inhibit atherosclerosis progression in experimental animals, being also able to stimulate reverse cholesterol transport in humans. Recently, high interest has been devoted to a molecular variant of apoA-I, apoA-I(Milano) (apoA-I(M)), characterized by a Cys for Arg substitution and formation of apoA-I(M)/A-I(M) dimers. These latter are characterized by a prolonged permanence in plasma and a more effective cholesterol removing function, which may offer an improved approach to the therapeutic management of arterial disease. Aside from a number of clinical studies on human apoA-I(M) carriers, all indicating a clear protection from cardiovascular disease in spite of markedly reduced HDL levels, animal investigations have provided definite indication as to the potential of apoA-I(M) infusion to directly reduce the extent of atherosclerotic plaques. In addition to the well known powerful cholesterol effluxing capacity of apoA-I(M), fibrinolytic properties and possibly antioxidant/vasodilator mechanisms seem to be in play. Ongoing clinical studies will provide final indication as to the potential of this new therapeutic approach.