Structural brain imaging abnormalities in schizophrenia-resemble spectrum disorders in many respects. Similar to schizophrenia, cerebrospinal fluid (CSF) is increased and cortical volumes are decreased in schizotypal personality disorder (SPD). In this large sample study, MRI assessed white matter volumes and diffusion tensor anisotropy was assessed in the schizophrenia spectrum. The sample includes 230 schizophrenics (ages 13-78) and an approximately age matched group of 81 patients with schizotypal disorder and 230 normal volunteers. For the bipolar spectrum there were 44 patients with bipolar spectrum disorder. Results in a pilot subsample of patients revealed increases in white matter in the cingulate in SPD and Schizophrenia in comparison to the normal sample. However in prefrontal regions, a schizophrenia spectrum pattern was observed with greater white matter increases in patients with schizophrenia than patients with schizotypal disorder, and greater gray matter decreases in patients with schizophrenia than patients with schizotypal disorder. Anisotropy changes were widely observed across the prefrontal cortex and corpus callosum. Taken together these results suggest that prefrontal change appears associated with a continuous spectrum deficit while some changes in the cingulate and other brain regions may show protective or reactive change in schizotypal patients. Bipolar patients had significantly reduced volume of the white and the gray matter of the frontal cortex. Furthermore, compared with control subjects, BPS patients as a group showed alterations in anisotropy of the internal capsule adjacent to the striatum and thalamus and the frontal white matter.