OBJECTIVES: Simvastatin, 40 mg, plus ezetimibe, 10 mg, daily, reduced the risk of cardiovascular events in stable patients with a history of acute coronary syndrome (ACS) in the Study of Vytorin Efficacy International Trial (IMPROVE-IT). Before the widespread use of Co-therapy with simvastatin and ezetimibe in such patients, its cost effectiveness should be demonstrated. Therefore, we investigated the cost effectiveness of adding ezetimibe to simvastatin treatment for patients with ACS in the United States. METHODS: A Markov state-transition model was developed to estimate the lifetime incremental cost effectiveness (in dollars per quality-adjusted years of life) associated with simvastatin compare with simvastatin plus ezetimibe co-therapy in patients with ACS. The model takes into account the increased risk of cardiovascular events due to increased age. The analysis was performed using a societal perspective in 2016. Direct medical cost, treatment costs and the costs of cardiovascular events, were included in the analysis. The robustness of the model to various assumptions was tested in a sensitivity analysis. Costs ($US, 2016 values) and outcomes were discounted at 3% per annum. RESULTS: In the IMPROVE-IT scenario, simvastatin resulted in lower QALYs with a value of 0.806, while Simvastatin plus ezetimibe resulted in 0.813 QALYs. Total costs were $8,483 for simvastatin and $9,459 for Simvastatin plus ezetimibe. Therefore, combination resulted in a gain of 0.007 QALYS at an additional cost of $975. The ICERs for combination compared with simvastatin alone was $30,855 per QALY. Based on willingness to pay threshold of $50,000 per QALY, the ICER for the combined therapy is not considered to be cost effective. Sensitivity analyses found that the model was sensitive to cost of ezetimibe. CONCLUSIONS: Co-therapy with simvastatin plus ezetimibe prevented cardiovascular risk in IMPROVE-IT; however, it appears to be not a cost-effective treatment compared with the simvastatin monotherapy in patients with histories of ACS in U. S.