Seven distinct 14-3-3 proteins are expressed in mammals. One of the 14-3-3 genes (eta) has been previously associated with decreased expression in the prefrontal cortex (PFC) of subjects with schizophrenia. DNA microarray analysis of the PFC of 10 subjects with schizophrenia and 10 matched controls indicated that the majority of 14-3-3 genes exhibited moderate to marked decreases in expression in schizophrenia, which were significant at the group level across all 10 comparisons (p<0.021). Selected changes in gene expression were further examined using in situ hybridization (ISH) in the same subject pairs as well as in four monkeys treated chronically with haloperidol and matched control animals. All analyses were performed blind to subject identity and diagnosis, or treatment. ISH analysis and multivariate analysis of covariance confirmed the significant decreases in expression of two 14-3-3 genes: beta -31.9%, zeta -18.2%. Two other 14-3-3 genes exhibited more modest decreases in expression levels that were significant only in pairwise comparisons that did not factor in post-mortem interval or tissue storage time: gamma -11.9%, eta -15.4%. In the PFC of haloperidol-treated monkeys, there was no difference in 14-3-3 zeta expression, while 14-3-3 beta increased 28% (p<0.05) as a result of neuroleptic treatment. Our results suggest that decreased expression of selected 14-3-3 genes is a common feature of schizophrenia and that the 14-3-3 beta transcript may be unique among the 14-3-3 genes in its increase in response to haloperidol and decrease in the disease state.