Abnormalities in the function of α-synuclein are implicated in the pathogenesis of Parkinson's disease (PD). We found that α-synuclein-deficient mice are resistant to MPTP-induced degeneration of dopaminergic neurons. There was dose-dependent protection against loss of both dopamine in the striatum and dopamine transporter (DAT) immunoreactive neurons in the substantia nigra. These effects were not due to alterations in MPTP processing. We found that α-synuclein-deficient mice are also resistant to both malonate and 3-nitropropionic acid (3-NP) neurotoxicity. There was reduced generation of reactive oxygen species in α-synuclein-deficient mice following administration of 3-NP. These findings implicate α-synuclein as a modulator of oxidative damage, which has been implicated in neuronal death produced by MPTP and other mitochondrial toxins.