Schizophrenia (SZ) is a severe mental illness with neuropathology in many regions, including the striatum. The typical symptoms of this disease are psychosis (such as hallucinations and delusions), cognitive impairments, and the deficit syndrome. Not all patients respond to treatment and, in those who do, only psychotic symptoms are improved. Imaging studies support a biological distinction between treatment response and resistance, but postmortem examinations of this issue are rare. This study tests the hypotheses that abnormalities in mitochondria, the energy producing organelles in the cell, may correlate with treatment response. Postmortem striatal tissue was obtained from the Maryland Brain Collection. The density of mitochondria (in various neuropil compartments) and the number of mitochondria per synapse (all types of synapses combined) were tallied using electron microscopy and stereology in striatum from SZ subjects (rated treatment responsive or not) and normal controls. The number of mitochondria per synapse was significantly different among groups for both the caudate nucleus (P < 0.025) and putamen (P < 0.002). Compared to controls, treatment-responsive SZ subjects had a 37-43% decrease in the number of mitochondria per synapse in the caudate nucleus and putamen. In the putamen, treatment-responsive subjects also had decreases in this measure compared to treatment-resistant subjects (34%). Our results provide further support for a biological distinction between treatment response and treatment resistance in SZ. Because treatment responders have fewer mitochondria per synapse than controls, although the treatment-resistant subjects have similar results to that of controls, fewer mitochondria per synapse may be related to treatment response. © 2010 Wiley-Liss, Inc.