A variety of cytoarchitectural disturbances have been described in limbic regions in postmortem studies of schizophrenia, many of which suggest a developmental disturbance of normal neuronal geometry. This geometry is established and maintained by elements of the neuronal cytoskeleton. Immunohistochemistry with a panel of 15 monoclonal antibodies was used to monitor the presence of neuronal cytoskeletal proteins in the hippocampal formations of six patients with schizophrenia, six normal controls, and six with neurodegenerative disorders. In five of the six subjects with schizophrenia, prominent and specific alterations were found in the distribution of two microtubule-associated proteins, MAP2 and MAP5, which were anatomically selective for the subiculum and entorhinal cortex. In contrast, the immunoreactivity of other cytoskeletal proteins (i.e., tau, tubulins, and selected neurofilament protein phosphoisoforms) was similar for all subjects. Defects in the expression of MAP2 and MAP5, two proteins that contribute to the establishment and maintenance of neuronal polarity, could underlie some of the cytoarchitectural abnormalities described in schizophrenia and impair signal transduction in the affected dendrites. The subiculum and entorhinal cortex interconnect the hippocampal formation with widespread cortices and subcortical nuclei and play important roles in higher cognitive functions. Hence, pathologic lesions that distort the polarized geometry of neurons could play a role in the emergence of aberrant behavior in schizophrenia.