1. 3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) exhibit a wide variety of anti-atherogenic effects that may be independent of their property to lower plasma cholesterol. 2. In order to systematically investigate these effects at a cellular level, we investigated gene expression in phorbol myristate acetate (PMA)-activated and non-activated human THP-1 monocytes in response to statins using cDNA arrays. 3. Of 588 genes tested, 26 were differentially expressed in the presence of statins. A marked reduction was found for the chemokine macrophage inflammatory protein-1alpha (MIP-1alpha). The decrease in MIP-1alpha mRNA expression after incubation with statins was confirmed by quantitative reverse transcription-polymerase chain reaction in THP-1 monocytes and human freshly isolated monocytes. Macrophage inflammatory protein-1alpha protein in THP-1 monocytes was reduced from 377 to 299 and 305 pg/mL by 0.1 micro mol/L simvastatin and 0.01 micro mol/L cerivastatin, respectively. The reduction in MIP-1alpha expression by statins was due, at least in part, to transcriptional inhibition of MIP-1alpha promoter activity. 4. The CC receptor ligand MIP-1alpha is a chemokine that has been implicated in atherosclerotic lesion formation. The present findings suggest that statin-mediated immunomodulation by inhibiting MIP-1alpha could contribute to the beneficial effects of statin therapy independent of lowering plasma cholesterol.