The fractional rate of cholesterol esterification in very low density lipoproteinand low density lipoprotein-depleted plasma (FERHDL) was studied in normolipidemic subjects and in individuals with hyperlipidemia and proven coronary artery disease (CAD). The FERHDLwas significantly higher than the FER in whole plasma and was significantly higher in normal men than in normal women. In addition, men and women with primary hyperlipidemia had significantly higher FERHDLvalues relative to their sex-matched controls. The most significant increases in FERHDLvalues, however, were observed in individuals with CAD. In all patient groups, FERHDLwas positively correlated with plasma triglyceride concentration. In addition, FERHDLwas negatively related to plasma high density lipoprotein (HDL) cholesterol concentration in all groups except in men with CAD and in normolipidemic women. The gradient gel electrophoretic pattern of HDL from individuals with either low or high FERHDLvalues indicated an inverse relation between this activity and the relative amount of HDL2bparticles. FERHDLlikely reflects the metabolic properties of the heterogeneous population of HDL particles in the plasma and may be a function of the relative content of larger and smaller HDL particles. It appears to be a sensitive and reliable functional measure of the particle size distribution in the HDL pool and one of potential clinical value in the assessment of risk for CAD.