Aortic and plasma lipid compositions were compared during a 12-month period in Watanabe heritable hyperlipemic (WHHL), comparably hypercholesterolemic fat-fed, and age-matched control normolipidemic rabbits to determine whether exposure to equivalent degrees of endogenous or exogenous hypercholesterolemia led to differences in the composition and concentration of lipids deposited in the artery wall. Although there were marked differences in the distribution of cholesterol among the lipoproteins in the WHHL versus the fat-fed rabbits, the contents of both free and esterified cholesterol were elevated to an equivalent degree in the aorta and plasma. In contrast, the triglyceride content of both the plasma and aorta were elevated only in the WHHL rabbits. However, aortic total phospholipids were increased in both the WHHL and fat-fed animals as compared to control rabbits. In the control rabbits, there was an age-dependent enrichment in aortic relative to plasma cholesteryl-oleate consistent with low density lipoprotein (LDL) receptor-directed intracellular cholesteryl ester processing. In contrast, enrichment in cholesteryl-oleate in aortae relative to plasma was not detected in either WHHL or fat-fed groups, suggesting that the plasma cholesteryl ester composition was the primary determinant of the aortic cholesterol composition. Thus, during chronic hypercholesterolemia, deposition of lipids in the artery wall appears to be determined by plasma lipoprotein levels and composition if the LDL receptor is either absent on a genetic basis or suppressed due to a high-fat, high-cholesterol diet.