Using positron emission tomography (PET) and [ 1 1 C]N-methylspiperone (NMSP), we examined 5-HT 2 receptors in the cortex of schizophrenic patients in whom we previously observed decereased prefrontal D1 receptor binding. The subjects were 10 neuroleptic-naive schizophrenic patients, 7 schizophrenic patients who were drug-free but had previously been treated with neuroleptics, and 12 normal controls. A non-significant trend towards decreased prefrontal [ 1 1 C]NMSP binding was observed in the neuroleptic-treated patients, suggesting a possible effect of previous neuroleptic treatment on the alteration in cortical 5-HT 2 function. However, the neuroleptic-naive patients showed no noticeable difference in cortical [ 1 1 C]NMSP binding compared to controls. Our results do not rule out the role of 5-HT 2 function as a crucial site of therapeutic activity of schizophrenia, but they do suggest that cortical 5-HT 2 receptors might not be primarily involved in the pathophysiology of schizophrenia.