Introduction : Bipolar disorder is a chronic disease characterized by periods of mania or hypomania, depression, or a combination of both (mixed state). Because bipolar disorder is one of the leading causes of disability, it represents an important economic burden on society. Asenapine (ASE) is a new second-generation antipsychotic developed and approved for the treatment of manic or mixed episodes associated with bipolar disorder. The objective of the present study was to assess the cost-effectiveness of ASE compared to olanzapine (OLA) in the treatment of patients experiencing mixed episodes associated with bipolar I disorder in the context of the Italian National Health Service (NHS). ; Methods : A pharmacoeconomic model was developed to simulate the management of Italian bipolar I patients with mixed episodes over a 5-year time horizon by combining clinical parameters with resource utilization. An expert panel of Italian psychiatrists and health economists was responsible for adapting a UK model to the Italian context. The primary outcome measure of the economic evaluation was the incremental cost effectiveness ratio, where effectiveness is measured in terms of quality adjusted life-years gained. Scenario analyses, sensitivity analyses, and a probabilistic sensitivity analysis were performed to test the robustness of the model. ; Results : This pharmacoeconomic model showed that ASE resulted to be dominant over OLA; in fact, ASE was associated with lower direct costs (derived largely by the savings from hospitalizations avoided) and also generated a better quality of life. Results were robust to changes in key parameters; both scenario analyses and sensitivity analyses demonstrated model reliability. ; Conclusions : Results from this study suggest that the management of bipolar I patients with mixed episodes using ASE as alternative to OLA can lead to cost saving for the Italian NHS and improve patients quality of life.