Postprandial triglyceride-rich lipoproteins (TRL)exert proatherogenic effects at the arterial wall, including lipid deposition. Following consumption of a mixed meal (1,200 kcal), plasma-mediated cellular free cholesterol (FC) efflux, lecithin:cholesterol acyltransferase (LCAT), and cholesteryl ester transfer protein (CETP) activities were determined in subjects (n ؍ 12) displaying type IIB hyperlipidemia and compared with those in a normolipidemic control group (n ؍ 14). The relative capacity of plasma to induce FC efflux from Fu5AH cells via the SR-BI receptor was significantly increased 4 h postprandially ( ؉ 23%; P Ͻ 0.005) in the type IIB group, whereas it remained unchanged for postprandial plasma from normolipidemic subjects. LCAT activity was significantly elevated 2 h postprandially in both the IIB and control groups, ( ؉ 46% and ؉ 36%, respectively; P Ͻ 0.005 vs. respective baseline value). In type IIB subjects, total cholesteryl ester (CE) mass transfer from HDL to total TRL [chylomicrons (CMs) ؉ VLDL-1 ؉ VLDL-2 ؉ IDL] increased progressively from 15 ؎ 2 g CE/h/ml at baseline to 28 ؎ 2 g CE transferred/h/ml ( ؉ 87%; P ؍ 0.0004) at 4 h postprandially. CE transfer to CMs and VLDL-1 was preferentially stimulated (2.6-fold and 2.3-fold respectively) at 4 h in IIB subjects and occurred concomitantly with elevation in mass and particle number of both CMs (2.3-fold) and VLDL-1 (1.3-fold). Furthermore, in type IIB subjects, CETP-mediated total CE flux over the 8 h postprandial period from HDL to potentially atherogenic TRL was significantly enhanced, and notably to VLDL-1 (32-fold elevation; P Ͻ 0.005), relative to control subjects. Such CE transfer flux was reflected in a significant postprandial increase in CE-TG ratio in both CMs and VLDL-1 in type IIB plasmas. In conclusion, HDL-CE is preferentially targeted to VLDL-1 via the action of CETP during alimentary lipemia, thereby favoring formation and accumulation of atherogenic CE-rich remnant particles. In order to maintain cholesterol homeostasis in peripheral tissues, excess cellular cholesterol is returned to the liver for excretion via a multistep process termed "reverse cholesterol transport" (RCT) (1). A key component of this process involves the transfer of a significant portion of the cholesteryl ester (CE) pool in HDL to apoB-containing lipoproteins (VLDL, IDL, and LDL) via the action of the cholesteryl ester transfer protein (CETP) (2).Hyperlipidemia of phenotype IIB is associated with an increased risk of premature coronary artery disease and is characterized by concomitant elevation of circulating levels of atherogenic apoB-containing, triglyceride-rich (VLDL) and cholesterol-rich lipoproteins (VLDL remnants, IDL, and LDL including small, dense LDL) (3). In type IIB hyperlipidemia during the fasting state, CETP is implicated in the intravascular formation of atherogenic small, dense LDL through an indirect mechanism involving an elevated rate of CE transfer from HDL to VLDL, and more specifically, to large VLDL-1 particles (4, 5)....