Parkinson's disease is a neurological disorder involving the progressive loss of dopaminergic neurons in the substantia nigra pars compacta. There is increasing evidence that inflammation plays a role in the propagation of neurodegenerative processes in Parkinson's disease. We investigated the neuroprotective effects of simvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A inhibitor with anti-inflammatory properties, in mice treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Oral administration of simvastatin attenuated the depletion of dopamine, 3,4-dihydroxyphenylacetic acid, and homovanillic acid in the striatum caused by MPTP in a dose-dependent manner. Simvastatin also inhibited the formation of 3-nitrotyrosine in striatal proteins in MPTP-treated mice. Simvastatin had no effect on cholesterol concentrations in the plasma or in the striatum. Simvastatin inhibited the production of tumor necrosis factor (TNF)-alpha, nitric oxide, and superoxide in cultured rat microglia stimulated by lipopolysaccharide. The results suggest that simvastatin inhibits the formation of TNF-alpha and peroxynitrite in activated microglia thereby protecting dopaminergic neurons from inflammatory damage. Simvastatin may be a potential new treatment to slow the progression of Parkinson's disease.