OBJECTIVES: Patients with schizophrenia suffer from numerous relapses and re-hospitalizations that will associate with high medical expense. Although the benefits of new generation of antipsychotic have been demonstrated over the last decade, the issues of patient compliance has become the main factor to the relapse. The long-acting risperidone is the only long acting atypical antipsychotic injectable agent which will show the benefit of improvement in compliance. To assist decision-making regarding the place of long-acting risperidone in therapy, a cost-effectiveness analysis of strategies involving first-line treatment with long-acting risperidone, oral olanzapine and quetiapine was performed from the perspective of Chinese healthcare system. METHODS: A decision analytical model was applied, rather than a real prospective clinical trial. The model used a time horizon of two years. The probabilities of treatment response of different agents and the relapse & hospitalization rates were estimated by an executive committee consisted of 17 randomly selected senior psychiatrists. The unit cost for each medical procedure was calculated from the price system database built by Chinese National Development and Innovation Committee and the medical resource consumption offered by the executive committee in Delphi survey. The principal efficacy measure was proportion of patients successfully treated, defined as those who responded to the initial treatment and had no more than two consecutive episodes of clinical deterioration and without needing a change of treatment over the 2-year period. Comprehensive sensitivity analysis was carried out to test the robustness of the model. RESULTS: The proportion of patients successfully treated over the 2-year period was 46.71% for long-acting risperidone, 39.93% for olanzapine, and 31.28% for quetiapine. The mean cost-effectiveness ratios were 189,427, 202,432, and 233,015 per successfully treated patient for long-acting risperidone, quetiapine and olanzapine, respectively. Results of the sensitivity analysis confirmed that the results were robust to a wide variation of different input variables. CONCLUSIONS: The results showed that long-acting risperidone is more cost-effective than either Olanzapine or quetiapine for patients with schizophrenia in long-term maintenance treatment.