Very low-density lipoprotein (VLDL) and LDL plasma levels are associated with cardiovascular mortality. Whereas VLDL/LDL lowering causes regression of early atherosclerotic lesions, less is known about the effects of aggressive lipid lowering on regression of advanced complex lesions. We therefore investigated the effect of VLDL/LDL lowering on pre-existing lesions in LDL receptor-deficient mice. Mice fed a highfat diet for 16 weeks developed advanced lesions with fibrous caps, necrotic cores, and cholesterol clefts in the brachiocephalic artery. After an additional 14 weeks on a low-fat diet, plasma cholesterol levels decreased from 21. Dyslipidemia is a central risk factor for cardiovascular disease and is the primary target for prevention of cardiovascular mortality.1 Modification of low-density lipoproteins (LDL) is considered a key contributor to cardiovascular disease in the general population.2 Furthermore, levels of VLDL/triglycerides are often elevated in patients with type 2 diabetes or the metabolic syndrome, 3 and increased level of triglycerides is considered a risk factor for atherosclerotic heart disease in patients with and without diabetes. 4,5 The great majority of acute clinical cardiovascular events, myocardial infarction and stroke, are believed to be caused by unstable atherosclerotic lesions.6,7 Studies of human atherosclerotic lesions have indicated that most clinically relevant lesions are composed of necrotic cores covered by thin fibrous caps containing macrophage-rich re-