Hydroxymethylglutaryl CoA (HMG CoA) reductase inhibitors, or statins, have been shown to reduce atherosclerotic cardiovascular morbidity and mortality. Atherosclerotic plaque lesions can be chronically inflamed and vulnerable to rupture or stable and less rupture-prone. Human smooth muscle cells (SMC) are critically important in maintaining the stability of atherosclerotic plaques. This stability may be greatly influenced by pro-inflammatory mediators such as IFN-gamma, TNF-alpha, and Il-1beta and Fas ligand (FasL) that are present in human atheroma. The purpose of the present study was to examine the effect of the statins on apoptosis of SMC. We have found that SMC are normally resistant to Fas or cytokine-induced apoptosis, but can be sensitized to these agents with pharmacological concentrations of some statins. Simvastatin and lovastatin strongly sensitized the cells to apoptotic agents while atorvastatin was less effective. In contrast to the lipophilic statins, the hydrophilic statin pravastatin did not induce this sensitization of SMC to apoptosis. Treatment of SMC with either mevalonate, the product of the HMG-CoA reductase, or geranylgeranylpyrophosphate, a down stream intermediate, prevented lipophilic statin-induced sensitization to apoptosis. These results suggest that prenylation of one or more proteins is critically involved in regulating the sensitivity of SMC to apoptotic stimuli. Our data support the emerging evidence that through this pathway the various statins may have effects which are beyond a simple lowering of the levels of circulating cholesterol.