The aim of this study was to investigate whether cerivastatin (BAYw6228), a new potent 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase inhibitor, was able to prevent atherogenesis in heterozygous Watanabe heritable-hyperlipidemic (WHHL) rabbits, a model never tested before using this HMG-CoA reductase inhibitor. The heterozygous WHHL rabbits of our breeding developed mild hypercholesterolemia along with focal atherosclerotic lesions in the thoracic aorta. A 9-week treatment with cerivastatin at doses comparable to those used in humans (50 μg/kg/day) reduced serum total cholesterol levels (from 94.4 ± 10.9 to 43.6 ± 10.5 mg/dl, p < 0.005) and prevented aortic lesion development (intima/media ratio: 0.058 ± 0.032 vs 0.946 ± 0.282 in the placebo group, p < 0.0005). Using a panel of monoclonal antibodies specific to macrophages and able to recognize different smooth muscle cell (SMC) phenotypes, we observed that cerivastatin treatment affected the differentiation properties of SMCs and drastically reduced SMC and macrophage accumulation in the intima of the thoracic aorta. These data show that in the presence of moderate atherosclerotic lesions, such as those of heterozygous WHHL rabbits, low doses of cerivastatin exert an antiatherogenic effect.