In a naturalistic study of the effectiveness of atypical antipsychotics for the long-term outpatient treatment of persons with severe and persistent mental illness, 19 patients began taking risperidone and were prospectively evaluated. Nine patients dropped out of risperidone treatment before three months; four of them later responded to clozapine. The ten patients who completed the study on risperidone were less severely ill at baseline. Three completers with unremitting negative symptoms required a combination of risperidone and typical antipsychotics. The results suggest that risperidone is effective for about half of patients with severe and persistent mental illness. Very ill patients who are not responsive to risperidone or combined antipsychotic therapy will likely benefit from clozapine.