Objective: We evaluated the efficacy of the potent antioxidant C3to salvage nigrostriatal neuronal function after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) exposure in nonhuman primates. C3is a first-in-class functionalized water-soluble fullerene that reduces oxygen radical species associated with neurodegeneration in in vitro studies. However, C3has not been evaluated as a neuroprotective agent in a Parkinson model in vivo. Methods: Macaque fascicularis monkeys were used in a double-blind, placebo-controlled study design. MPTPlesioned primates were given systemic C3(n = 8) or placebo (n = 7) for 2 months starting 1 week after MPTP. Outcomes included in vivo behavioral measures of motor parkinsonism using a validated nonhuman primate rating scale, kinematic analyses of peak upper extremity velocity, positron emission tomography imaging of 6-[18F]fluorodopa (FD; reflects dopa decarboxylase) and [11C]dihydrotetrabenazine (DTBZ; reflects vesicular monoamine transporter type 2), ex vivo quantification of striatal dopamine, and stereologic counts of tyrosine hydroxylase-immunostained neurons in substantia nigra. Results: After 2 months, C3-treated monkeys had significantly improved parkinsonian motor ratings, greater striatal FD and DTBZ uptake, and higher striatal dopamine levels. None of the C3-treated animals developed any toxicity. Interpretation: Systemic treatment with C3reduced striatal injury and improved motor function despite administration after the MPTP injury process had begun. These data strongly support further development of C3as a promising therapeutic agent for Parkinson disease.