Apolipoprotein A-I (apoA-I) is a 243 amino-acid cysteine deficient protein, containing 10 amphipathic domains, that allow its binding to a lipid-rich surface. It is the major protein component of high-density lipoproteins (HDL). Each HDL contains 2 or 3 copies of apoA-I plus various combinations of additional apolipoproteins (e.g. apoE, apoA-IV, apoA-II), lipid transport proteins (e.g. CETP and PLTP), and surface acting enzymes (e.g. paraoxonase, LCAT, PAF). This heterogenous and dynamic class of lipoproteins mainly functions in reverse cholesterol transport, a process resulting in the net removal of excess cholesterol from tissues, to be transported to the liver for excretion. The apolipoprotein AIMilano (A-IMilano) is a rare and naturally occurring variant form of the native apoA-I. The A-IMilano variant was a chance discovery in an individual with very low HDL-cholesterol (7-10 mg/dL) compared to the normal human levels of 40-50 mg/dL. This clinical observation dates back 30 years, and was accompanied by similar findings in two of the probands children as well as in his father. Surprisingly, these carriers appeared to be remarkably free from any vascular abnormalities. Extensive studies led to the identification of the mutation, a Cysteine for Arginine substitution at position 173, i.e. the first description of a human apolipoprotein mutation associated to altered lipoprotein composition and metabolism. This led to an extensive evaluation of the population of Limone sul Garda for the presence of the mutation and the cardiovascular disease status of the population, confirming the earlier suggestion that this might be a protective variant. In the past 25 years some important additional insights were provided. Particularly, it could be shown that the HDL containing AIMilano is endowed with a remarkably enhanced capacity to remove cholesterol from tissues. "HDL therapy" is a novel and emerging area of therapeutic development in the cardiovascular field. It attempts to supplement and improve the vascular benefit exerted by other agents active on lipid metabolism, ie hypolipidemic drugs. Further, it takes advantage on novel techniques of coronary evaluation. A number or reports have examined the potential therapeutic properties of synthetic HDL prepared by complexing recombinant apo A-IMilano with phospholipids. The availability of synthetic HDL complexes containing recombinant apoA-IMilano has opened a new era of therapeutic management of coronary disease. Prototype HDL formulations of recombinant apoA-IMilano/phospholipid complexes have used dipalmitoylphosphatidylcholine (DPPC) or 1-palmitoyl-2-oleyl phosphatidylcholine (POPC) as phospholipid component. HDL containing apoAIMilano/ DPPC have clearly shown rapid regression of a focal carotid atheroma in a rabbit model. The mechanism of this very rapid effect appears to be associated with the cholesterol removing capacity and extended serum half-life of HDL containing A-IMilano. In a pilot study, ETC-216 (apoA-IMilano/POPC) similarly showed significant reduction of coronary plaque burden after five weekly treatments as assessed by intravascular ultrasound (IVUS) in patients with acute coronary syndromes. It is likely that additional safety, efficacy and dose regimen studies in a larger patient population will need to be performed to fully evaluate the potential of this agent as an "HDL therapy" product candidate. "HDL therapy" such as ETC- 216 is being evaluated for use with the current standard of care for patients with acute coronary syndromes, including the use of statins.