To test the hypothesis that depressed and schizophrenic patients have a common pathophysiological mechanism for hypofunction of the prefrontal cortex (‘hypofrontality’), we measured regional cortical blood flow (rCBF) in ten depressed patients, ten patients with schizophrenia, and 20 age- and sex-matched normal controls. Blood flow was measured during three different cognitive conditions: a resting state, a simple number-matching sensorimotor control task, and the Wisconsin Card Sorting test (WCS). The schizophrenic patients had lower prefrontal rCBF during the WCS. There were no differences in global or regional flow between the depressed patients and the normal subjects during any testing condition. Analysis of rCBF lateralisation showed that during the WCS normal subjects had relatively more left parietal blood flow than depressed patients, who had more right parietal blood flow. Since the testing condition that has most consistently revealed hypofrontality in schizophrenia (i.e. the WCS) was not associated with abnormal rCBF in the depressed patients, these data suggest that the pathophysiological mechanisms underlying prefrontal hypofunction in depression and schizophrenia are different.