The neural mechanisms that mediate a primate model of tardive dyskinesia have been investigated using the 2-deoxyglucose (2-DG) uptake technique. Three groups of Cebus monkeys were used. Some of the animals received long-term neuroleptic treatment. These animals were allotted to one of two groups depending on whether they developed tardive dyskinesia or not. A third group of animals served as untreated controls. The neuroleptic-treated dyskinetic animals showed reduced uptake of 2-DG in the medial segment of the globus pallidus and in the ventral anterior (VA) and ventral lateral (VL) nuclei of the thalamus relative to that seen in the equivalent structures in the neuroleptic-treated nondyskinetic and untreated control animals. The data are interpreted as suggesting that tardive dyskinesia is mediated by underactivity of the pathways from the subthalamic nucleus to the medial pallidal segment and the substantia pars nigra pars reticulata, which in turn result in a loss of gamma-aminobutyric acid-ergic inhibition of the VA and VL thalamic nuclei. This suggests that tardive dyskinesia shares a common underlying neural mechanism with other hyperkinesias such as chorea and ballism.