BACKGROUND: The comparatively high acquisition costs of the new antipsychotic drugs have induced the mental health community to look closely at their potential benefits. OBJECTIVE: To compare the clinical and economic outcomes associated with olanzapine, risperidone and typical neuroleptics treatment for schizophrenia. METHODS: A multicenter, observational, two-years long, retrospective and prospective study was conducted with 229 psychotic patients (in charge by psychiatric Centers of Regione Sicilia -Italy). Clinical outcomes were assessed using changes in CGI (Clinical Global Impression) and PANSS (Positive and Negative Syndrome Scale) scores. The economic data collection included pharmacological and non-pharmacological resources consumption (hospitalizations, medical/nurse visits, etc.). The economic evaluation was conducted in the perspective of the Local Psychiatric Services. RESULTS: The results in terms of clinical performance indicated an advantage (statistically significant) in the olanzapine group of patients. The pharmacological costs were significantly lower (p<0,05) in the typical group due to the cheaper acquisition cost of these drugs while total treatment costs were similar between the three groups (p>0,05). Treatment with olanzapine was associated with a lower non-pharmacological resources consumption and showed a general reduction (p<0,05 vs. risperidone) of total treatment costs between 1st and 2nd year of observation. CONCLUSIONS: Within the context of the local health care Services, olanzapine appears to be the "dominant" therapeutic option compared with risperidone and typical neuroleptics. Treatment with risperidone appears to be "cost-neutral" compared with typical neuroleptics.