OBJECTIVE: The authors hypothesized that cortical gray matter volume reduction in schizophrenia is greatest in the heteromodal association cortex. This area comprises a highly integrated, reciprocally interconnected system that coordinates higher order cortical functions. METHOD: Total brain and regional gray matter volumes were calculated in 46 schizophrenic patients and 60 age and sex-matched comparison subjects by using magnetic resonance images. Disease specificity was examined by assessing 27 patients with bipolar disorder. Approximations to the dorsolateral prefrontal cortex, inferior parietal lobule, and superior temporal gyrus were selected as regions of interest for the heteromodal association cortex. Occipital and sensorimotor areas were used as comparison regions to test the hypothesis for regional specificity. RESULTS: Gray matter volume was reduced in schizophrenic patients in index regions even after covariance for overall brain volume, sex, and age. Bipolar disorder patients did not exhibit heteromodal gray matter reduction. Comparison regions did not differ among the three groups. Global gray matter volume was not different among groups after covariance for global brain volume. Comprehensive individual region post hoc analysis found no additional gray matter differences. CONCLUSIONS: These findings support the theory of disproportionate reduction of gray matter volume in the heteromodal association cortex specific to schizophrenia.