The objective of the study was to examine whether patients with schizophrenia who were judged to be stable on long-term treatment with conventional antipsychotic medications would further benefit from a switch to an atypical antipsychotic drug. Thirty-six subjects with schizophrenia spectrum disorder, on conventional antipsychotic medication therapy for at least 2 years, were randomized in double-blind fashion to risperidone versus olanzapine. Patients were titrated up to 6 mg risperidone or 15 mg olanzapine as tolerated, followed by tapering and discontinuation of conventional antipsychotic medication. Atypical antipsychotic agents were then administered alone (monotherapy) for 12 weeks. Efficacy and tolerability were assessed using the Positive and Negative Syndrome Scale (PANSS), Clinical Global Impression Scale, and Simpson Angus Scale. Body weight was measured at each visit. Both treatment groups exhibited marked and similar improvement in the total PANSS score from baseline to study endpoint (22 weeks) [risperidone: baseline=59.3 (SE 3.1), 22 weeks=44.3 (SE 2.3) (p<0.001); olanzapine: baseline=55.9 (SE 3.3), 22 weeks=46.9 (SE 3.2) (p<0.001). Both groups also exhibited significant reductions in PANSS factor scores for positive and negative symptoms and disorganized thoughts. Only risperidone-treated patients exhibited significant decreases in uncontrolled hostility/excitement and anxiety and depression. Of note, while positive factor scores exhibited the majority of change within the first 10 weeks, negative factor scores continued to decline significantly in both treatment groups throughout the study. Tolerability assessments did not differ between groups. The results indicate that both atypical antipsychotic medications provided significant additional improvement in symptom severity in patients with schizophrenia previously on conventional antipsychotic agents.