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OBJECTIVE: The purpose of this investigation was to evaluate the effects of clozapine and risperidone on spatial working memory in patients with schizophrenia. METHOD: Spatial working memory performance was evaluated at baseline and after 17 and 29 weeks in 97 patients with schizophrenia participating in a multisite trial. RESULTS: Compared with baseline performance while receiving conventional antipsychotic medication, risperidone improved, and clozapine worsened, spatial working memory performance. CONCLUSIONS: The differential effects of these medications on spatial working memory may be due to the anticholinergic effects of clozapine and prefrontal dopamine-enhancing effects of risperidone.