OBJECTIVES: The aim of the study was to estimate the cost-effectiveness relation of the long-acting injection formulation of Risperidone (LARI) IM every 2 weeks vs oral antipsychotics Olanzapine and Risperidone and the traditional prolonged-action antipsychotic injection formulation of haloperidol depot in the pharmacological management of schizophrenia in Mexico. Consequently, a pharmacoeconomic study was proposed using a cost-effectiveness model in adult patients treated in the Mexican Social Security Institute (IMSS) METHODS: A decision analysis was developed using a retrospective and comparative cost-effectiveness model over a 24 month period. A sample of Schizophrenic patients was obtained using IMSS databases and a decision tree based on relapses, hospitalization, pharmacological treatment, hospital discharges and re-hospitalizations. To determine the criteria for the effectiveness of each alternative, a meta-analysis was carried out based on national and international literature taking the clinical outcomes: total PANSS, changes in body weight, AE, adherence, hospitalization, re-hospitalization and relapses. The factors for costs were: specific pharmacological therapy, outpatient consultations for treatment, basal hospitalization, re-hospitalization, length of hospital stay and absence from work. The decision tree was validated by a panel of experts. RESULTS: Risperidone LA was the alternative with the lowest cost for annual treatment ($84,877 pesos). Differences versus the other treatment therapies were found in regards to hospitalization, subsequent hospitalizations and, to a lesser degree, absenteeism from work. Treatment with LARI produced savings of $8,324 pesos compared to Haloperidol Depot (the most widely used injected antipsychotic in Mexico); compared to the second generation antipsychotics (atypical), savings were $27,733 pesos versus Olanzapine and $1,875 pesos versus oral Risperidone. LARI produced the lowest number of re-hospitalized patients and events requiring re-hospitalization as well as superior clinical improvements compared to the other therapies. CONCLUSION: The study demonstrated that LARI is a cost-efficient and dominant alternative for the treatment of schizophrenia patients in Mexico.