Several studies with functional and structural brain-imaging techniques support the hypothesis that responders and non-responders to clozapine could show a different pattern of cerebral dysfunction. Thirty-nine neuroleptic-refractory schizophrenic patients were studied with 99Tc-labelled hexamethyl-propylene-aminoxime (HMPAO) and SPECT, while on classical neuroleptics and after 6 months of treatment with clozapine. The perfusion differences between responders and non-responders to clozapine were studied in the regions included within the dorsolateral and orbitofrontal fronto-striato-thalamic circuits, as well as the predictive value of these parameters. These values were compared to those of a normal database, and between both treatments within the two groups. On-neuroleptic perfusion in non-responders was lower in the thalamus, basal ganglia and dorsolateral prefrontal cortex. Thalamus and right prefrontal perfusion regions were selected as response predictors by a discriminant analysis. Thalamic and left basal ganglia activities while on neuroleptics were lower only in non-responders with respect to the normal subjects. Perfusion changes were only observed in the responder group in thalamus and basal ganglia. Study of regional perfusion may contribute to the prediction of clozapine response.