OBJECTIVES: Given the changing statin marketplace, this study compares the cost-effectiveness among generic statins (lovastatin, pravastatin, simvastatin) and more effective branded monotherapy statins (atorvastatin, rosuvastatin) for first and second tier placement consideration, respectively, in routine clinical practice. METHODS: Retrospective electronic medical record database study was conducted of newly prescribed statin therapy during August 2003-March 2005. Effectiveness of each statin in reducing LDL-C and attaining National Cholesterol Education Panel Adult Treatment Panel III LDL-C goal was evaluated using multivariate regressions after adjusting for baseline LDL-C, demographics, comorbidities, and therapy duration. Cost-effectiveness from a payer perspective was estimated for rosuvastatin and atorvastatin (branded statins), and separately for lovastatin, simvastatin and pravastatin (generic statins). Annualized costs for statin (wholesale acquisition cost, WAC) and titration were included. RESULTS: Of 10,421 eligible patients, adjusted LDL-C reduction was significantly greater (p<0.001) with rosuvastatin (-31.6%) than atorvastatin (-21.9%) and other generic statins (-19.1% to -13.9%). Average dose of rosuvastatin was 12 mg vs. 17-35 mg for other statins. Among patients not at goal at baseline, the adjusted percentage of moderate/high risk patients attaining LDL-C goal was higher (p <0.001) for rosuvastatin (76.1%) versus atorvastatin (72.6%) and other statins (57.6%-65%). Rosuvastatin was more effective and less costly than atorvastatin in terms of cost per patient reaching goal (in high and moderate risk patients) and in terms of percent LDL-C lowering. Simvastatin and pravastatin required a discount greater than 61% and 71%, respectively, from the branded WAC to achieve cost per unit of LDL-C reduction lower than generic lovastatin. CONCLUSION: To facilitate effective and efficient management of patients with dyslipidemia, a tiered formulary could include generic simvastatin or pravastatin as the cost-effective generic statin in the first tier (depending upon level of discount to current WAC) and rosuvastatin as the cost-effective branded statin in the second tier.