Elevated plasma cholesteryl ester transfer protein (CETP) mass is characteristic of combined hyperlipidaemia (CHL), an atherogenic dyslipidaemia characterized by increased levels of both very low-density lipoprotein (VLDL) and low-density lipoprotein (LDL) and subnormal levels of high-density lipoprotein (HDL). CETP remodels plasma lipoproteins by promoting the heteroexchange of neutral lipids. To determine the mechanism of the CETP-mediated redistribution of cholesteryl ester (CE) between plasma lipoprotein particles in CHL, we measured CE mass transfer and exchange from HDL to apoB-containing lipoproteins under physiological conditions in the plasmas of 14 CHL patients and compared the data with those in a group of normolipidaemic subjects (NLS; n = 9). The rate of CE mass transfer from HDL to VLDL was significantly increased in CHL patients (24.1 +/- 3.8 micrograms CE transferred h-1 mL-1 plasma) when compared with NLS (14.4 +/- 2.6 micrograms CE transferred h-1 mL-1 plasma, P = 0.0001). By contrast with control subjects, no net CE mass transfer from HDL to LDL was detected in CHL patients; transfer of radiolabelled CE to LDL was, however, observed, suggesting the occurrence of CE exchange between HDL and LDL in the absence of net CE mass transfer. The LDL fraction from CHL patients displayed a significant reduction (15%; P < 0.003) in its ability to accept cholesteryl ester from HDL when compared with normolipidaemic LDL. Moreover, a reduction of 10% (P < 0.02) was found in the capacity of hyperlipidaemic HDL to donate cholesteryl esters to apoB-containing lipoproteins as compared with control HDL; the reduced levels (-32%) of HDL2b particles in CHL plasmas may account for this effect. We conclude that the low affinity of hyperlipidaemic LDL particles for CETP, taken together with the elevated plasma concentrations of a qualitatively active CE acceptor, VLDL, and the low HDL levels in CHL patients, result in the absence of net CE mass transfer from HDL to LDL in Combined hyperlipidaemia.