Neuroimaging studies have implicated the prefronto-striatal loop as a substrate for the cognitive deficits in schizophrenia (SCHZ). Postmortem morphometric studies reveal that layers III and V of the dorsolateral prefrontal cortex (dlPFC), which gave rise to glutamatergic projections to neostriatum, demonstrate the most structural pathology in this region of the SCHZ. These neuronal alterations in SCHZ are not accompanied by marked glial changes as revealed by Nissl staining. We examined the glial-type specific pathology in SCHZ by analyzing the glial fibrillary acidic protein- (GFAP) immunoreactive astroglia in contrast to the Nissl-stained general pool of glial cells in dlPFC (area 9) from 9 subjects with SCHZ and 15 psychiatrically normal control subjects. In layer V of the dlPFC in SCHZ, there was a significant 32% reduction in the GFAP-area fraction, 81% increase in the density of the GFAP-positive cell bodies and a 14% decrease in the width of the cortical layer V, as compared to the control subjects. None of these parameters were affected in layers III and IV in the SCHZ. Therefore, only subtle, type- and layer-specific glial pathology is present in the dlPFC in SCHZ. Astroglial pathology in dlPFC may reflect disturbances of the neuron-glia interactions in layer V and may be related to the dysfunctional prefronto-striatal circuits, dopaminergic alterations and cognitive pathology in SCHZ.