We studied the effect of a single oral fat load, supplemented with retinyl palmitate (RP), on high density lipoprotein (HDL) lipids in six normolipidemic men with coronary artery disease (CAD) and in six age- and lipid-matched controls. All subjects were selected from a study group which underwent the same protocol 2 years earlier. Post-prandial total plasma lipids, plasma RP levels, and HDL lipids were evaluated at 2-h intervals up till 10 h after the meal. In most subjects the post-prandial response of plasma triglyceride (TG) and plasma RP was identical in the first and second tests. Following the fat load, control subjects showed no change in HDL total cholesterol (TC) or HDL cholesteryl ester (CE) and showed an increase in HDL-TG. CAD subjects however showed a decrease in HDL-TC and HDL-CE and an increase in HDL-TG, similar to the increase in control subjects. In control subjects an increase in HDL phospholipid (PL) was apparent between 0 and 8 h after the fat load. By contrast, in CAD subjects the increase in HDL-PL was only found after as long as 6 h. The magnitude of the post-prandial response of HDL-PL measured during the test was significantly lower in the CAD group. The effects of the fat load on HDL free cholesterol (FC) were similar to the changes in HDL-PL. These data support the hypothesis that PL and FC released during the degradation of chylomicrons as surface remnants are taken up by HDL. This process is clearly delayed in normolipidemic CAD subjects compared with controls. The data suggest that differences in the post-prandial response to an oral fat load in normolipidemic CAD patients and control subjects are not confined to the clearance of TG-rich lipoproteins, but also involve a difference in the uptake of chylomicron surface material by HDL.