OBJECTIVES: Health economic assessment of cost-effectiveness parameters for the comparison of typical (Haloperidol), partially atypical depot (Flupentixol) and atypical neuroleptics (Olanzapin, Risperidon) in the treatment of schizophrenia from the perspective of German health insurance. METHODS: A published markov model was rebuilt and calibrated with DATA®, taking into consideration relapse rates, extrapyramidal symptoms (EPS) and other prognostic symptoms. All data were derived from published sources where available. Besides the comparison of monotherapy, a stepwise treatment scenario was simulated, starting with three months Olanzapin treatment followed by Flupentixol. Over the 5-year simulation period cumulated complication rates (percentage of relapse, positive and negative symptoms), patient related outcomes (Brief Psychiatric Rating Score “BPRS”) and cost parameters (medication, EPS-cost and total costs) were assessed. A cost-effectiveness analysis was performed. RESULTS: Olanzapin/Flupentixol in combination had the lowest relapse rate (42.9 %), followed by Flupentixol (44.4%), Olanzapin (44.8%), Risperidon (48.0 %) and Haloperidol (57.6%). Olanzapin treatment showed the highest BPRS score (3.13), followed by Risperidon (3.07), Olanzapin/Flupentixol (2.52), Flupentixol (2.42) and Haloperidol (2.37). The most cost-effective treatment measured by cost in DEM per relapse free patient was Olanzapin/Flupentixol (200,000), followed by Olanzapin (211,000), Flupentixol (212,000), Risperidon (231,000) and Haloperidol (287,000). The best cost-effectiveness (expressed in DEM/BPRS) was observed in Olanzapin (37,100), followed by Risperidon (39,100), Olanzapin/Flupentixol (45,500), Flupentixol (48,600) and Haloperidol (51,400). Total 5-year drug cost (DEM) were 24,600, 26,800, 3,800, 2,700 and 3,210 respectively. CONCLUSIONS: In terms of relapse rates Olanzapin and Flupentixol lead to better clinical outcome and better cost-effectiveness results as compared to alternative typical or atypical neuroleptic therapy. With Olanzapin and Risperidon most favorable BPRS scores were achieved. Flupentixol depot as monotherapy or following initial Olanzapin treatment is a cost-effective alternative to atypical neuroleptics at low drug cost and low relapse rates.