Objective: To assess the cost-effectiveness of LDL cholesterol reduction based upon the 2004 NCEP guideline update for atorvastatin, lovastatin, rosuvastatin, simvastatin, atorvastatin plus ezetimibe, lovastatin plus extended-release niacin, and simvastatin plus ezetimibe from a third-party payer's perspective. Methods: Literature-based decision analyses were conducted to evaluate direct costs, treatment outcomes defined as LDL goals of <70 and <100 mg/dl, and clinically-significant adverse events. Each of the decision trees consisted of four initial monotherapy treatment arms and also considered combination therapy versus dose titration if treatment goals were not achieved. Base cases were defined according to NCEP high-risk patient classifications and five categories of baseline LDL levels from the 1999-2002 National Health and Nutrition Examination Survey (NHANES). Meta-analyses were performed to estimate percent LDL reductions for each agent and for each dose. Monte Carlo simulations and probabilistic sensitivity analyses were used to yield incremental cost-effectiveness ratios, confidence intervals, and graphical representations of findings. One-way sensitivity analyses were conducted on key variables of uncertainty and costs. Results: Overall, costs were observed to higher and effectiveness lower among patients seeking a <70 mg/dl goal. Simvastatin was found to be the most cost-effective treatment option for both <70 mg/dL and <100 mg/dl goals and for each baseline LDL cholesterol strata. Combination therapy was more cost-effective compared to dose titration among the <70 mg/dl goal and in those requiring LDL reductions above 45%. Analyses indicated that the recent generic pricing of simvastatin substantially impacted results. Conclusion: From a third-party payer perspective and among high-risk patients, simvastatin (including monotherapy and combination with ezetimibe), was observed to be the most cost-effective treatment option for LDL treatment goals of <70 and <100 mg/dl. Further research is warranted concerning combination therapies and in evaluating additional surrogate outcomes such as high-density lipoprotein (HDL).