OBJECTIVE: To assess the cost-effectiveness (CE) of rosuvastatin compared to atorvastatin and simvastatin in high-risk patients in routine clinical practice. METHODS: Medical charts of 24,225 patients with Coronary Heart Disease (or its equivalent) were reviewed at 500 physician offices in the Midwest. Patients between the ages of 18 and 79 years who initiated either atorvastatin, rosuvastatin or simvastatin treatment; and had a lipid panel within 90 days before and 4 weeks after initiating statin therapy were included in the study. Effectiveness [reduction in low density lipoprotein cholesterol (LDL-C) and achievement of National Cholesterol Educational Program Adult Treatment Panel III LDL-C goal] estimates were derived using multivariate approach. Annual direct medical costs [wholesale acquisition cost of statins and titration] were included. A decision analytic CE model, from payer perspective, was constructed to compute incremental cost effectiveness ratios (ICERs) in terms of incremental cost/incremental percent change in LDL-C and incremental cost/incremental percent of patients reaching goal for rosuvastatin compared to atorvastatin and simvastatin. RESULTS: Rosuvastatin patients (n=63) were slightly younger and had higher baseline LDL-C, than either atorvastatin (n=480) or simvastatin (n=232) patients. In the base case analysis, rosuvastatin had lowest overall annualized cost followed by atorvastatin and simvastatin. Using adjusted effectiveness estimates, as compared to atorvastatin and simvastatin, rosuvastatin had the lowest cost/LDL-C reduction ($33.27 and $55.43 vs. $23.9, respectively), and cost/LDL-C goal attainment ($1708 and $2893 vs. $1260, respectively). Incremental CE analysis indicated that rosuvastatin dominated both atorvastatin and simvastatin. A significant reduction in price of simvastatin was required to attain the same level of CE as rosuvastatin. Results were most sensitive to acquisition costs of statins. CONCLUSION: Rosuvastatin is cost-effective as compared to atorvastatin and simvastatin in terms of cost per LDL-C reduction, and cost per patient reaching goal in managing hyperlipidemia among high-risk patients in routine clinical practice.