OBJECTIVES: The purpose of this study was to investigate the likelihood of achieving both LDL and HDL goals in the primary prevention of cardiovascular disease using an epidemiologic sample of United States residents by comparing simvastatin to a combined regimen of lovastatin/extended-release niacin. An additional objective was to estimate the cost-effectiveness of each product and the incremental cost-effectiveness ratio between regimens. METHODS: A decision analytic model was developed to compare the cost-effectiveness of simvastatin and lovastatin/extended-release niacin. Product labeling estimated the change in cholesterol concentrations and the frequency of clinically important adverse events. The Third National Health and Nutrition Examination Survey (NHANES) adult data were used to estimate population cholesterol levels. Average wholesale price was used for medication costs. RESULTS: The NHANES data revealed there were 256 patients (10.5%) that required a LDL goal of < 160 mg/dL, 1268 (52.2%) that required a goal of < 130 mg/dL, and 906 patients (37.3%) that required a goal of < 100 mg/dL. For both the 130 mg/dL and 100 mg/dL LDL goal analyses (and HDL =40 mg/dL), lovastatin/extended-release niacin had higher success rates and lower average total costs than simvastatin. Simvastatin had the highest success rate in achieving LDL level < 160 mg/dL and HDL =40 mg/dL. However, the average total health system cost (medications, physician visit costs, and laboratory costs) to use simvastatin was approximately twice that of lovastatin/extended-release niacin ($665 versus $332). CONCLUSIONS: For LDL goals < 130 and < 100 mg/dL (and HDL =40 mg/dL), lovastatin/extended-release niacin was both more successful and less costly than simvastatin.