Effective medical management of levodopa-induced dyskinesia (LID) remains an unmet need for patients with Parkinson disease (PD). Changes in opioid transmission in the basal ganglia associated with LID suggest a therapeutic opportunity. Here we determined the impact of modulating both mu and kappa opioid receptor signaling using the mixed agonist/antagonist analgesic nalbuphine in reducing LID and its molecular markers in the nonhuman primate model.,1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated macaques with advanced parkinsonism and reproducible LID received a range of nalbuphine doses or saline subcutaneously as: (1) monotherapy, (2) acute coadministration with levodopa, and (3) chronic coadministration for 1 month. Animals were assessed by blinded examiners for motor disability and LID severity using standardized rating scales. Plasma levodopa levels were determined with and without nalbuphine, and postmortem brain samples were subjected to Western blot analyses.,Nalbuphine reduced LID in a dose-dependent manner by 48% (p < 0.001) without compromising the anti-PD effect of levodopa or changing plasma levodopa levels. There was no tolerance to the anti-LID effect of nalbuphine given chronically. Nalbuphine coadministered with levodopa was well tolerated and did not cause sedation. Nalbuphine monotherapy had no effect on motor disability. Striatal tissue analyses showed that nalbuphine cotherapy blocks several molecular correlates of LID, including overexpression of ΔFosB, prodynorphin, dynorphin A, cyclin-dependent kinase 5, and increased phosphorylation of DARPP-32 at threonine-34.,Nalbuphine reverses the molecular milieu in the striatum associated with LID and is a safe and effective anti-LID agent in the primate model of PD. These findings support repurposing this analgesic for the treatment of LID.,© 2015 American Neurological Association.