An understanding of the development of tardive dyskinesia (TD) may require prospective studies assessing the relationship of brain function measures to behavior. This study was undertaken to determine whether predisposition to the development of TD is related to abnormalities of cerebral 18F-labeled 2-fluoro-2-deoxy-D-glucose (FDG) positron emission tomography (PET) measures in schizophrenia. A group of 42 patients without TD underwent FDG PET scanning for measuring cerebral metabolism as well as neuropsychological evaluation and magnetic resonance imaging. Patients were assessed longitudinally for TD development. Eight patients developed TD within 3 years. They were matched to eight patients without TD. Glucose metabolic rates and region/ whole brain ratios were examined in 38 regions of interest per hemisphere. Whole brain metabolism did not differ between the two groups. However, relative hypermetabolism in temporolimbic, brainstem, and cerebellar regions and hypoactivity in parietal and cingulate gyrus were found in the patients who later developed TD in contrast to those who did not. The groups were matched on clinical measures and had similar neuropsychological and neuroanatomic testing results. Thus, differences in the metabolic activity of specific brain regions are associated with vulnerability to TD development.