OBJECTIVES: To assess the clinical, functional, and economic ramifications of switching antipsychotics for any cause during treatment of schizophrenia. METHODS: We used outpatient data from a randomized, open-label, one-year cost-effectiveness trial of olanzapine, risperidone, and typical antipsychotics in the treatment of schizophrenia. Study protocol permitted switching of antipsychotics when clinically warranted. Resource utilization was abstracted from medical records. Treatment outcomes were assessed with standard psychiatric measures. Changes from pre-to-post switch were assessed among patients who switched from randomized antipsychotics. Switchers and non-switchers were compared on risk for crisis-related events (e.g., hospitalization). RESULTS: About one-third of the patients (30.2%, 185/612) were switched from randomized antipsychotics: 14.9% from olanzapine, 27.9% from risperidone, and 48.5% from typical antipsychotics. Following antipsychotic switch, switchers experienced significant improvements in symptoms and social relations (p<0.001), and numerical cost reductions ($3.72 per day less, p=0.320). Compared to non-switchers, switchers were at significantly higher risk for crisis-related events (p=0.006), experienced them sooner (p=0.004), and accrued higher crisis-related service costs (p<0.05). CONCLUSIONS: Although switching antipsychotics is an effective ²rescue² option, it is costly in personal and economic terms. The optimal treatment strategy is to begin treatment with the antipsychotic most likely to lead to effective treatment for each individual patient.