OBJECTIVE: The goals of this study were 1) to determine the extent of substance abuse in patients with treatment-resistant schizophrenia and 2) to assess the relevance of such abuse to subsequent response to treatment with clozapine. METHOD: The subjects were 118 treatment- resistant patients with DSM-III-R diagnoses of schizophrenia or schizoaffective disorder who underwent detailed demographic, clinical, and psychopathological evaluations before commencing treatment with clozapine. Lifetime and current histories of substance abuse were also systematically evaluated and characterized according to the Research Diagnostic Criteria and DSM-III-R. Response to clozapine treatment at 6 months was determined with measures of psychopathology and psychosocial function. RESULTS: An antecedent or current history of substance abuse was determined for 29 patients. Although predominantly male, the abusers did not differ from the nonabusers on other demographic features. The substance abusers actually showed less psychopathology (negative and disorganization symptoms) and better psychosocial functioning at baseline; however, both groups attained similar improvements on these measures after 6 months of clozapine therapy. CONCLUSIONS: A modest extent of previous or current substance abuse was observed among neuroleptic-resistant schizophrenic patients who subsequently received treatment with clozapine. This antecedent history of substance abuse did not appear to negatively influence subsequent response to clozapine treatment.