Primates and rodents show marked differences in sensitivity to the neurotoxic effects of MPTP. We and others have previously shown that the toxic effects of MPTP on nigrostriatal cells are dependent on the oxidative metabolism of MPTP to the quaternary species MPP+. We have therefore compared the distribution and metabolism of MPTP in the monkey and several rodent species. Three major differences have been identified: 1) the primate, but not the rodents, showed a persistently high concentration of MPTP metabolites in the caudate nucleus compared to other brain regions; 2) the rodent brains cleared MPTP and its metabolites much more rapidly than did the monkey, and; 3) the predominant metabolite retained by the monkey brain was MPP+, while MPP+ cannot be detected in rodent brains for more than a few hours after injection. The persistence of MPP+ in the primate brain may explain the heightened toxicity of MPTP in this species.