Conventional wisdom suggests that halting or reversing long-term atherosclerosis requires increasing the amount of circulating high-density lipoprotein (HDL) coursing through the vasculature. However, recent evidence seems to indicate that reducing the size of cholesterol-containing lipid plaques might be accomplished by methods that either do not raise or, in fact, lower the amount of circulating HDL. Carriers of apoAI(Milano), a variant of apoprotein AI (a component of HDL), have reduced levels of circulating low-density lipoprotein (LDL). Intriguingly, these individuals have reduced amounts of circulating HDL and total apoAI. Infusions of the ApoAI(Milano) variant given to patients with coronary atherosclerosis appear to lead to disease regression and reduced plaque size. However, larger studies are required to provide definitive proof of apoAI(Milano)'s benefits. What is certain is that attention should be focused on the removal of cholesterol from plaques rather than simply desiring to raise HDL concentrations in patients.