The expression of tissue factor (TF), mainly by infiltrated inflammatory cells, has been shown to be responsible for the thrombogenicity associated with atheroma. The contribution of the nonlipid-related effects of statins to the clinical benefits of statin therapy is currently under intense investigation. In this study, we evaluated the ability of fluvastatin to modulate TF expression and macrophage accumulation in rabbit carotid intimal lesions independently of cholesterol lowering. Male rabbits were fed for 30 days a 1% cholesterol-rich diet with or without fluvastatin at 5 mg/kg per day. Two weeks from the start of treatment, a silastic collar was placed around the carotid artery. Fifteen days later, the animals were killed, and carotid segments were excised and processed. The atherogenic diet caused a consistent increase in plasma cholesterol levels (610±231 mg/dL versus 50±9 mg/dL at baseline), which were not affected by fluvastatin (603±248 mg/dL). In the rabbits fed a high cholesterol diet without fluvastatin, an intimal lesion with macrophage accumulation and TF expression was detected. Fluvastatin significantly reduced TF and macrophage content of the lesion (−50% for both). Results indicate that fluvastatin may attenuate the inflammatory and thrombogenic potential of atherosclerotic lesions through a mechanism(s) other than cholesterol reduction, providing new insight regarding the complex mode of action of statins.