Statins, inhibitors of HMG-CoA reductase. have pleiotropic benefits independent of cholesterol levels, including anti-oxidant and anti-inflammatory effects. Here, we investigate the effect of statins on myeloperoxidase (MPO) expression. MPO expressed in foam cell macrophages, was recently shown to oxidize the ApoA-1 component of HDL, impairing, ABCA-1 Mediated cholesterol efflux. High levels of serum MPO correlate with increased risk of CAD events. Findings here show that statins strongly inhibit MPO mRNA expression in human and murine monocyte-macrophages. Suppression was reversed by downstream intermediates of HMG-CoA reductase, mevalonate, and geranylgeranylpyrophosphate, but not farnesylpyrophosphate, An inhibitor of geranylgeranyltransferase, GGTI-286 mimics the effects of statins. indicating geranylgeranylation is key to MPO expression. Reduction of MPO mRNA levels was observed in vivo in leukocytes from statin-fed mice. correlating with reductions in MPO protein and enzyme activity. These findings suggest that the pleiotropic protections afforded by statins may be due in part to suppression of MPO expression. © 2005 Elsevier Inc. All rights reserved.