Schizophrenic brains exhibit various neuro-pathological changes in size, volume and structure as compared to normal brains. These structural abnormalities could be the result of apoptotic cell death. ARTS/Sept4 protein plays an important role in induction and promotion of apoptosis. Though ARTS is highly expressed in the healthy human brain, most of tested schizophrenic brain samples showed no expression of ARTS protein. Specifically, using Western blot analysis with monoclonal anti-ARTS antibody we found that only 1 out of 14 schizophrenic samples (7%) showed a strong ARTS signal as compared to 10 out of 15 (66.6%) found in the normal controls group. Furthermore, using immunohistochemistry assay only 33.3% (5 of 15) (SE+/-12.5) of the schizophrenic patients samples showed any ARTS immunoreactivity as compared to (13 of 15) 87% (SE+/-9) of bipolar, (11 of 14) 78% (SE+/-11.3) of major depression and (10 of 14) 71% (SE+/-12.5) of normal controls. A four-fold reduction in apoptosis rate was measured in these schizophrenic samples as compared to average apoptosis rate found in all other samples. These data support the linkage between loss of ARTS expression and the loss of sensitivity towards apoptosis. Interestingly, levels of ARTS were significantly lower in male schizophrenic patients as compared to female schizophrenic patients, and males of all other control groups. We propose that ARTS may play an important role in the pathogenesis of schizophrenia and could be used as a marker for this disease.