OBJECTIVE: This economic analysis examined the implications of using ezetimibe/simvastatin (E/S) as first-line cholesterol therapy compared to usual care with statin monotherapy. METHODS: The analysis consisted of: 1) a comparison of the annual drug costs and percent LDL cholesterol (LDL-C) reduction for E/S and all statins/all doses; and 2) a model of a hypothetical population of 1000 untreated coronary heart disease (CHD) patients prescribed either E/S 10/20 or usual care with statin monotherapy for five years. The model examined the cost offsets or savings for E/S 10/20 compared to usual care, estimated on a per patient basis due to projected differences in cardiovascular disease (CVD) related hospitalization costs plus drug costs (wholesale acquisition costs or WAC). Sensitivity analyses included comparing E/S 10/20 with atorvastatin, and varying drug acquisition costs. Key parameters of the model were as follows: Usual care was assumed to provide LDL-C reduction based upon the market-share weighted average of the reported efficacy for each statin. A log-linear regression based on end-point trials estimated the relationship between LDL-C and CVD event rates. The cost per patient with an event was estimated to be $22,430 based upon analysis of CVD hospitalizations in managed care claims. RESULTS: First, based upon WAC, the annual drug cost per person for E/S was calculated as $842. For high-efficacy statins/doses (>40% LDL-C reduction), the annual drug costs per person were $1080 (atorvastatin), $1379 (simvastatin), and $803 (rosuvastatin). Second, compared to usual care for five years of treatment, E/S 10/20 was estimated to result in cost savings of $1568 per patient. Sensitivity analyses conducted also showed cost savings for E/S. CONCLUSION: Compared to usual care with statin monotherapy, treatment with E/S 10/20 was estimated to reduce CVD events and hospitalizations among untreated CHD patients. This is projected to result in cost savings over five years.