Dehydroepiandrosterone has been recently recognized as neuroactive steroid with several vital neurophysiological activities on membrane receptors, such as N-methyl-d-aspartate, and gamma-aminobutyric acid receptors and on genomic androgen receptors. DHEA does also have an antiglucocorticoid effect. So far, the relevance of this neuroactive steroid to psychiatric disorders is not well known. In this study, plasma levels of DHEA were determined with a highly sensitive and specific gas-chromatography/mass-spectrometry method in 23 outpatients suffering from Diagnostic and Statistical Manual of Mental Disorders-IV schizophrenia compared with 23 healthy control subjects matched for age and sex. Plasma levels of DHEA were found to be strongly elevated in the group of schizophrenic patients (mean+/-SD=90.9+/-61.4 nmol/l) compared to that of control subjects (mean+/-SD=24.0+/-17.9 nmol/l) and the difference was highly significant (t=5.018, df=44, p<0.0001). This statistically significant difference was also found when we divided the groups of schizophrenics and controls in subgroups of males (t=4.536, df=24, p=0.0001) and females (t=2.777, df=18, p=0.0124). These results suggest that DHEA may have some role in the pathophysiology of schizophrenia due to its complex mechanism of action in the brain involving genomic and non-genomic components. Therefore, its study may provide further understanding of the pathophysiology of psychoses and open new avenues for their treatment.