Subtraction ictal single photon emission tomography (SPET) co-registered to magnetic resonance imaging (SISCOM) is an ictal-interictal brain perfusion SPET subtraction method, developed for evaluation of brain perfusion changes applied for the identification of epileptic foci. The aim of this study was to test whether regional cerebral blood flow (rCBF) alterations due to clozapine in schizophrenic patients could also be detected with SISCOM. We have studied the brain perfusion SPET data obtained both before (pre-SPET) and 8 weeks after (post-SPET) clozapine treatment, in 20 patients with schizophrenia. These data were used for SISCOM processing. In order to identify any alterations in the perfusion pattern using SISCOM, pre- and post-SPET data were subtracted from each other. Activation maps were created and merged on either pre- or post-SPET images. Visual interpretation of brain perfusion SPET studies were performed and compared with SISCOM findings. We found that final SISCOM images and visual evaluation of pre- and post-SPET studies were well concordant in 17/20 patients. Discordance was observed in 3 patients. In 1 of these 3 patients alterations observed with SISCOM were confirmed as subtle changes on visual re-evaluation of the image;. In the remaining 2 of these 3 patients, SISCOM did not confirm the changes observed by visual analysis. Additionally, SISCOM depicted perfusion alteration in occipital cortex in 5 patients. In conclusion, the algorithm of SISCOM seemed to be useful and complementary to visual evaluation, to assess rCBF changes due to clopazine in outpatient schizophrenic patients who had treatment refractoriness or intolerance of previous antipsychotics and to provide additional information when both pre- and post-SPET data were subtracted from each other.