Dysfunction of the dorsal prefrontal cortex (PFC) in schizophrenia may be associated with alterations in the regulation of brain metabolism. To determine whether abnormal expression of genes encoding proteins involved in cellular metabolism contributes to this dysfunction, we used cDNA microarrays to perform gene expression profiling of all major metabolic pathways in postmortem samples of PFC area 9 from 10 subjects with schizophrenia and 10 matched control subjects. Genes comprising 71 metabolic pathways were assessed in each pair, and only five pathways showed consistent changes (decreases) in subjects with schizophrenia. Reductions in expression were identified for genes involved in the regulation of ornithine and polyamine metabolism, the mitochondrial malate shuttle system, the transcarboxylic acid cycle, aspartate and alanine metabolism, and ubiquitin metabolism. Interestingly, although most of the metabolic genes that were consistently decreased across subjects with schizophrenia were not similarly decreased in haloperidol-treated monkeys, the transcript encoding the cytosolic form of malate dehydrogenase displayed prominent drug-associated increases in expression compared with untreated animals. These molecular analyses implicate a highly specific pattern of metabolic alterations in the PFC of subjects with schizophrenia and raise the possibility that antipsychotic medications may exert a therapeutic effect, in part, by normalizing some of these changes.