Given the beneficial effects of HMG-CoA reductase and ACAT inhibitors on hypercholesterolemia and atherosclerosis, we hypothesized that coadministration would improve the hypolipidemic response and not only limit lesion development but also alter the cellular composition of atherosclerotic lesions so as to induce a stable atherosclerotic lesion morphology. Plasma total cholesterol exposure was reduced 29 and 39% with atorvastatin (2.5 mg/kg) and CI-976 (5 mg/kg), respectively, and 60% upon coadministration due primarily to reductions in VLDL-cholesterol. Modest changes in liver cholesterol ester (CE) content were observed with atorvastatin or CI-976; however, a striking 48% reduction was noted upon coadministration. Liver HMG-CoA reductase mRNA levels were reduced 73% by cholesterol feeding and drug treatment did not prevent the reduction; however, atorvastatin alone and upon coadministration blunted the decrease in LDL receptor mRNA levels. The CE content of the iliac-femoral was unaffected by atorvastatin but was reduced 35% by CI-976 and 53% upon coadministration. Thoracic aortic CE content was reduced 38% by atorvastatin, 48% by CI-976 and 80% upon coadministration. Iliac-femoral lesion and macrophage area were reduced 48 and 67% by atorvastatin, respectively, and 68 and 81% by CI-976 but upon coadministration only an 85% reduction in macrophage area was noted. Aortic arch cross-sectional lesion and macrophage area were unaffected by atorvastatin, decreased 72-80% by CI-976 and reduced 87-92% upon coadministration. We conclude that inhibition of HMG-CoA reductase and ACAT acts synergistically to lower plasma total and lipoprotein cholesterol levels and to limit the development of atherosclerotic lesions in the cholesterol-fed rabbit by presumably regulating cholesterol trafficking pathways within liver and vascular cells.