Compliance to treatment is a key success factor to reduce hospitalisations in schizophrenic patients. Conventional antipsychotics (e.g., haloperidol) are effective in reducing positive symptoms of schizophrenia, and can cause multiple side effects (extrapyramidal symptoms, tardive dyskinesia). Atypical antipsychotics with daily oral administration (risperidone, olanzapine, clozapine) show improved efficacy and tolerability compared to conventional neuroleptics. Conventional depots have been shown to increase compliance and reduce the risk of relapse over oral conventional treatments. Long-acting risperidone (LA-RIS), administered intramuscularly once every two weeks, is the first to combine the benefits of a long-acting formulation with those of an atypical antipsychotic. OBJECTIVE: To assess cost-effectiveness of LA-RIS versus oral olanzapine (OLA) and haloperidol decanoate (HAL-D) in recently diagnosed schizophrenic patients in the perspective of the Italian National Health care System (NHS). METHODS: A French decision tree model was adapted to the Italian setting: outcome probabilities and cost estimates were based on published data, and supplemented with expert opinion. Only direct medical costs were considered. For LA-RIS (not yet marketed in Italy), 3 different price hypotheses were tested (€100-125-150/injection q2weeks). Effectiveness measures were relapse-free patients and patients maintained on the same treatment for 2 years. RESULTS: LA-RIS was found dominant versus HAL-D in all three hypotheses tested. Versus OLA (10mg/day), LA-RIS cost-effectiveness ratios ranged from dominance to a maximum of €17,544/2 years per incremental relapse-free patient. Sensitivity analysis showed that results were robust over a wide range of parameters tested, including variation of the daily dose of OLA to account for current medical practice in Italy according to the results of the RODOS papers (13.5mg/day). CONCLUSIONS: The model indicates that in recently diagnosed patients, LA-RIS is cost-saving versus HAL-D and cost-saving/cost-effective vs OLA and should be preferred as a treatment option over oral atypicals and conventional depots, in the perspective of the Italian NHS.