OBJECTIVES: Long-acting risperidone demonstrated in clinical studies to lead to improved adherence, reduced relapse and improved clinical and economic outcomes for schizophrenia patients. According to Brazilian treatment guidelines, olanzapine, ziprasidone and quetiapine are reserved as last option for refractory schizophrenic patients. The objective of this study was to evaluate the cost-effectiveness of long-acting risperidone compared to these oral atypicals in refractory schizophrenic patients. METHODS: Based on Edwards et al 2005, we developed a decision-analytic model, using Monte Carlo simulation, describing the clinical evolution of refractory schizophrenic patients over 2-years from the Brazilian public healthcare perspective. In year one, patients receive one of the studied drugs. In year two, partially compliant and non-compliant patients receiving oral atypicals were switched to long-acting risperidone; the long-acting risperidone patients continued on their treatment. The model estimates compliance, relapse (requiring or not requiring hospitalization), costs and cost-effectiveness (in terms of relapses avoided) of long-acting risperidone treatment versus olanzapine, quetiapine and ziprasidone. Clinical parameters and resource use were derived from the Edwards study and Brazilian medical literature. Brazilian government psychiatric program costs were applied. Sensitivity analyses were performed for key parameters. RESULTS: Over a 2-year horizon and simulating 1,000 patients as a base case, long-acting risperidone generated fewer relapses (30%), fewer hospitalizations (29%) and more compliant patients (68%) than the oral atypicals. Long-acting risperidone was also less costly compared to olanzapine (R$ 7.497.181,85), quetiapine (R$ 3.448.577,36) and ziprasidone (R$ 2.377.063,28). Long-acting risperidone is therefore a dominant therapeutic option compared to oral atypical antipsychotics. These results are in line with those reported in other countries. CONCLUSION: The utilization of long-acting risperidone is predicted to result in better clinical outcomes and lower total healthcare costs compared to oral atypicals used for refractory schizophrenia. Long-acting risperidone may be a cost-saving therapeutic option for Brazilian refractory schizophrenic patients.