Low density lipoprotein receptor (LDLr) is critical for plasma lipoprotein clearance and a decreased LDLr expression has been thought to explain the increased plasma cholesterol and atherosclerosis risk in humans with apolipoprotein (apo) E4. However, in mice expressing human apoE4 instead of their mouse counterpart, increased LDLr expression caused accumulation of cholesterol-rich apoE-poor chylomicron remnants, and resulted in significant atherosclerosis. The production rates of chylomicrons and very low density lipoproteins (VLDL) were unchanged, as was the clearance rate of exogenously given apoE-deficient remnants. These data suggest an enhanced conversion of nascent lipoprotein particles to cholesterol-rich remnants that are poorly cleared. We hypothesize that the negative effects from increased LDLr are due to the high binding affinity of apoE4 for the receptor which reduces the availability of apoE4 for transfer to triglyceride-rich lipoproteins (TRL), thereby inhibiting their rapid internalization.