OBJECTIVES: Metabolic syndrome (MetS) is a medical condition that may arise during exposure to antipsychotics and carries with it an increased risk of diabetes and cardiovascular disease (CVD). Asenapine is the first tetracyclic antipsychotic to treat manic episodes of Bipolar I Disorder (BD- I). In a head-to-head non-inferiority trial versus olanzapine, post-hoc analyses illustrate the higher incidence of developing MetS with olanzapine than with asenapine, already after 12 weeks of treatment. The aim of this study was to assess the cost-effectiveness of asenapine in the treatment of BD-I manic episodes compared to atypical antipsychotics with a focus on the long-term consequences of MetS over lifetime horizon.  METHODS: A Markov health-state cohort model was developed. Because similar efficacy in treating manic episodes was demonstrated in active controlled non-inferiority clinical trial vs. olanzapine and through indirect comparisons with quetiapine and aripiprazole, only the consequences of MetS were considered for this model. The risks of developing MetS after 12 weeks of treatment were derived from randomized clinical trials. The subsequent risks of developing diabetes or cardiovascular disease were based on previously published risk models. The perspective of the UK National Health Service (NHS) was applied and a lifetime horizon adopted. Deterministic and probabilistic sensitivity analyses were conducted. RESULTS: Asenapine dominates (more effective and less expensive) olanzapine, quetiapine and aripiprazole over lifetime horizon. Compared to treatment with generic olanzapine, and branded aripiprazole and quetiapine, asenapine was associated with incremental total costs of -£121, -£312 and -£560 respectively. Asenapine was associated with Quality-Adjusted Life Year gains of 0.0569 compared to olanzapine and quetiapine, and 0.0038 compared to aripriprazole. CONCLUSIONS: The significant lower incidence of developing MetS associated with asenapine compared to olanzapine, aripriprazole and quetiapine is associated with a lower incidence of diabetes and CVD that results in lower subsequent treatment costs and improved morbidity.