BACKGROUND: Previous studies suggest that the impact of early insults predisposing to schizophrenia may have differential consequences by sex. We hypothesized that brain regions found to be structurally different in normal men and women (sexual dimorphisms) and abnormal in schizophrenia would show significant sex differences in brain abnormalities, particularly in the cortex, in schizophrenia. METHODS: Forty outpatients diagnosed as having schizophrenia by DSM-III-R were systematically sampled to be comparable within sex with 48 normal comparison subjects on the basis of age, ethnicity, parental socioeconomic status, and handedness. A comprehensive assessment of the entire brain was based on T1-weighted 3-dimensional images acquired from a 1.5-T magnet. Multivariate general linear models for correlated data were used to test for sex-specific effects regarding 22 hypothesized cortical, subcortical, and cerebrospinal fluid brain volumes, adjusted for age and total cerebrum size. Sex x group interactions were also tested on asymmetries of the planum temporale, Heschl's gyrus, and superior temporal gyrus, additionally controlled for handedness. RESULTS: Normal patterns of sexual dimorphisms were disrupted in schizophrenia. Sex-specific effects were primarily evident in the cortex, particularly in the frontomedial cortex, basal forebrain, cingulate and paracingulate gyri, posterior supramarginal gyrus, and planum temporale. Normal asymmetry of the planum was also disrupted differentially in men and women with schizophrenia. There were no significant differential sex effects in subcortical gray matter regions or cerebrospinal fluid. CONCLUSION: Factors that produce normal sexual dimorphisms may be associated with modulating insults producing schizophrenia, particularly in the cortex.