Novel acyl coenzyme A:cholesterol acyltransferase (ACAT) inhibitor pactimibe was administered as the sulfate salt form to 3-month-old homozygous Watanabe heritable hyperlipidemic (WHHL) rabbits at doses of 0, 10, or 30 mg/kg for 32 weeks. Pactimibe (10 and 30 mg/kg) tended to reduce intimal thickening in thoracic aortic lesions (294+/-39 and 276+/-32 microm, respectively, versus 313+/-37 microm control), histopathological examination revealing significantly increased smooth muscle cell area (12.0+/-0.9% and 12.3+/-0.5%, P<0.05, respectively, versus 9.7+/-0.8% control), significantly increased collagen fiber area (20.5+/-1.2% and 31.0+/-1.3%, P<0.05, respectively, versus 16.2+/-1.0% control), and tended to reduce macrophage infiltration (6.0+/-1.1% and 4.6+/-1.0%, respectively, versus 7.0+/-1.3% control). Pactimibe dose-dependently reduced cholesteryl ester content in thoracic and abdominal aortic lesions, and reduced free cholesterol content in the aorta versus control. Although pactimibe did not alter serum cholesterol levels in WHHL rabbits, it stabilized vulnerable plaque characterized with reduced cholesteryl ester content, enriched collagen fibers and increased smooth muscle cells, indicating potential as a treatment strategy for coronary heart disease.