The National Institutes of Health's Adult Treatment Panel III (ATP-III) guidelines define the population of hypercholesterolemic patients for whom drug therapy is suggested. A wide body of evidence indicates that elevated low-density lipoprotein (LDL-C) is a major risk factor for coronary heart disease (CHD). Thus, the ATP-III guidelines target LDL-C levels for reduction in hypercholesterolemic patients in an effort to reduce CHD risk. The drug of choice is an HMG-CoA Reductase Inhibitor (statin), which has demonstrated effectiveness in reducing LDL-C. OBJECTIVES: To determine if the relative cost-effectiveness of the 3 most commonly prescribed statins is affected by the initial LDL-C and ATP-III goals. METHODS: A Monte Carlo simulation was used to model therapeutic course to target using data from published trials including (pre-treatment LDL-C distributions, expected LDL-C reduction by drug and dose and ATP-III LDL-C goals). Data from this model were entered into a cost-effectiveness analysis model in Data 4.0 (TreeAge Software, Inc, 2001). One-way sensitivity analyses were conducted upon pre-treatment LDL-C distribution, statin performance, and costs of: drugs, time away from work/home, office visits, laboratory tests and mono-therapy failure. RESULTS: Atorvastatin dominated the model, having the lowest drug cost and failure rate, regardless of initial LDL-C level or ATP-III guideline goal. Base case (mean LDL-C 188.9 mg/dl [SD 24.0] and goal LDL-C of 100 mg/dl) cost-effectiveness ratios for atorvastatin, simvastatin and pravastatin were $(US) 1,721, $(US) 3,641 and $(US) 22,029 respectively. Alternative case (mean LDL-C 149.6 mg/dl [SD 16.8] and goal LDL-C of 100 mg/dl) cost-effectiveness ratios for atorvastatin, simvastatin and pravastatin were $(US) 965, $(US) 1,552 and $(US) 2,498 respectively. CONCLUSIONS: Atorvastatin was the most cost-effective treatment among the tested statins. Cost-effectiveness rankings were insensitive to all tested variables. Cost-effectiveness was primarily determined by the performance characteristics of each drug and drug cost.