NK-104 ((+)-monocalcium bis(3R,5S,6E)-7-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolyl]-3,5-dihydroxy- 6-heptenoate), CAS 147526-32-7) an inhibitor of 3-hydroxy-3-metylglutaryl coenzyme A reductase, was administered in drinking water (0.5 mg/kg equivalent) to Watanabe heritable hyperlipidemic (WHHL) rabbits for 26 weeks. It lowered plasma total cholesterol (TC, 7-20%) and triglyceride (TG, 16-39%) levels throughout the experimental period due to a significant reduction of very low density lipoprotein cholesterol (VLDL-C, 61-62%, p < 0.05), intermediate density lipoprotein cholesterol (IDL-C, 49-60%, p < 0.05), VLDL-TG (40-53%, p = 0.06-0.08) and IDL-TG (29-59%, p = 0.06-0.14); low density lipoprotein cholesterol (LDL-C) was not affected. The pattern of the lipoprotein reduction along with a decrease in liver cholesteryl ester (CE, 33.1%, p < 0.01) suggests an intense reduction of VLDL secretion and a marginal induction of LDL-receptor. Enhanced expression of LDL receptor-related protein (LRP) in the liver was observed at mRNA levels (49.5% increase, P = 0.13), which might play a role in the lipoprotein reduction. Histological analyses of aorta revealed that aortic arch showed the most advanced lesions with larger lesion area (70.0 vs 41.3%) and much greater CE content (more than 2 fold) with less macrophages than thoracic aorta. NK-104 decreased the surface lesion area at the arch (23.1%, p = 0.054) and reduced the degeneration of media in the thoracic aorta (69.9% increase in medial smooth muscle cells, p < 0.01). Thus NK-104 preferentially reduced TG-rich lipoproteins (VLDL and IDL) without affecting LDL-C levels and prevented progression of atherosclerosis in WHHL rabbits.