We investigated the combined effect of dietary supplementation with l-arginine, which is the precursor of NO, and pharmacological treatment with atorvastatin, which is a 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase inhibitor, on the development of atherosclerosis in homozygous Watanabe heritable hyperlipidaemic rabbits. Rabbits were fed either standard rabbit chow (group C; n 9) as control, a 1·5 % l-arginine diet (group A; n 9), standard rabbit chow plus atorvastatin (2·5 mg/kg per d) in drinking water (group S; n 8), or standard rabbit chow plus a 1·5 % l-arginine diet with atorvastatin (group SA; n 8). Blood was sampled at 2-week intervals. After 8 weeks (T8), the aorta was harvested for topographic and histological analysis. Only the SA group showed decreases in total area of lesions (21 %) and the area of abdominal lesions (44 %) compared with the control group (P = 0·019). Furthermore, plaques in the SA group were smaller and less thick than those observed in the S group. Unexpectedly, plasma nitrite + nitrate levels were not modified under either the l-arginine diet alone or under l-arginine plus atorvastatin. The present study is the first to demonstrate that diet supplementation with l-arginine associated with a statin (atorvastatin) is more efficient in reducing lesion size than treatment with l-arginine or a statin alone. This is a relatively novel therapeutic approach associating a macronutrient and a drug.