Background: The liver is a key organ in lipid and lipoprotein metabolism. It has been postulated that a small diameter of sinusoidal fenestrae retards clearance of chylomicron remnants, resulting in hypercholesterolemia and atherosclerosis. However, this hypothesis has not been rigorously tested hitherto. Methods: In the current study, we compared plasma levels of pro-atherogenic lipoproteins and assessed the development of atherosclerosis at distinct locations throughout the arterial tree in heterozygous low density lipoprotein receptor deficient New Zealand White (NZW) and Dutch Belt (DB) rabbits with an average fenestrae size of 103 and 124 nm, respectively. Results: Feeding of a 0.15% cholesterol diet for 4 months resulted in similar total plasma cholesterol levels in NZW (420 ± 20 mg/dl) and DB (380 ± 30 mg/dl) rabbits. Following isolation of lipoproteins by ultracentrifugation, no biologically significant differences of very low density lipoprotein, intermediate density lipoprotein and low density lipoprotein cholesterol levels were observed between cholesterol fed NZW and DB rabbits. Furthermore, the relative amount of intestinally derived, apolipoprotein B48 containing lipoproteins did not differ significantly between both strains (7.2 ± 0.94 vs. 8.3 ± 1.2%). Atherosclerosis was more pronounced in the thoracic aorta in NZW rabbits than in DB rabbits but the reverse was observed in the abdominal aorta. These topographic differences cannot be explained by circulating lipoprotein levels. Conclusions: The data presented in this study do not support the hypothesis that the diameter of fenestrae is an important determinant of chylomicron remnant levels, diet-induced hypercholesterolemia and atherosclerosis in cholesterol-fed rabbits.