Objective-This study examines the effects of pharmacological inhibition of cholesteryl ester transfer protein (CETP) on the ability of high-density lipoprotein particles (HDL) to promote net cholesterol efflux from human THP-1 macrophage foam cells. Methods and Results-Two groups of 8 healthy, moderately hyperlipidemic subjects received the CETP inhibitor torcetrapib at 60 or 120 mg daily for 8 weeks. Torcetrapib increased HDL cholesterol levels in both groups by 50% and 60%, respectively. Compared with baseline, torcetrapib 60 mg daily increased HDL-mediated net cholesterol efflux from foam cells primarily by increasing HDL concentrations, whereas 120 mg daily torcetrapib increased cholesterol efflux both by increasing HDL concentration and by causing increased efflux at matched HDL concentrations. There was an increased content of lecithin:cholesterol acyltransferase (LCAT) and apolipoprotein E (apoE) in HDL-2 only at the 120 mg dose. ABCG1 activity was responsible for 40% to 50% of net cholesterol efflux to both control and T-HDL. Conclusions-These data indicate that inhibition of CETP by torcetrapib causes a modest increase in the ability of HDL to promote net cholesterol efflux at the 60 mg dose, and a more dramatic increase at the 120 mg dose in association with enhanced particle functionality. The HDL-mediated removal of excess free cholesterol (FC) from macrophage foam cells is thought to play a major role in the protection against the development of atherosclerosis. 2 However, current therapies for raising HDL are limited. Despite the favorable effects of statins on coronary heart disease, these agents have only modest effects on HDL-C levels. 3,4 Fibrates and niacin can raise HDL-C, but the increases are rarely Ͼ30% and only some of the fibrate trials have shown prevention of coronary events in patients with low HDL, and niacin is often not well tolerated. 5,6 Novel targets to raise HDL-C have emerged from the recent understanding of HDL synthesis, maturation, and catabolism. In humans, cholesteryl ester (CE) generated by the lecithin:cholesterol acyltransferase (LCAT) enzyme in HDL is transferred to apoB-lipoproteins by the cholesteryl ester transfer protein (CETP). CETP promotes the removal of cholesteryl ester (CE) from antiatherogenic HDL to atherogenic apoB-containing particles in exchange for triglycerides (TGs). 7 The marked increase in HDL cholesterol associated with human deficiency of CETP has suggested CETP inhibition as a potential strategy to treat atherosclerotic disease. 8,9 However, there has been concern that HDL particles accumulating in CETP deficiency might be dysfunctional. 10 We recently reported that large CE-rich HDL particles from 4 subjects with complete CETP deficiency (CETP-D) showed increased ability to promote cholesterol efflux from macrophage foam cells. 11 Central to this observation was the key role of LCAT and apolipoprotein E (apoE) present at high levels in CETP-D HDL driving net cholesterol efflux. Cholesterol efflux from cells to HDL can occur by passive diffusion...