Oxidative stress is implicated in the death of dopaminergic neurons in sporadic forms of Parkinson's disease. Because oxidative stress can be modulated endogenously by uncoupling proteins (UCPs), we hypothesized that specific neuronal expression of UCP2, one member of the UCP family that is rapidly induced in the CNS following insults, could confer neuroprotection in a mouse model of Parkinson's disease. We generated transgenic mice overexpressing UCP2 in catecholaminergic neurons under the control of the tyrosine hydroxylase promoter (TH-UCP2). In these mice, dopaminergic neurons of the substantia nigra showed a twofold elevation in UCP2 expression, elevated uncoupling of their mitochondria, and a marked reduction in indicators of oxidative stress, an effect also observed in the striatum. Upon acute exposure to 1,2,3,6-methyl-phenyl-tetrahydropyridine, TH-UCP2 mice showed neuroprotection and retention of locomotor functions. Our data suggest that UCP2 may represent a drug target for slowing the progression of Parkinson's disease.