OBJECTIVES: To assess the effects of various lipid-modifying strategies on direct medical costs of coronary heart disease (CHD) events among a representative patient cohort with established CHD. METHODS: Model-based analysis, using data from clinical trials, published literature, and national databases to project CHD medical costs (emergency, inpatient, and outpatient) over 5 years. The analysis focused on hypothetical cohorts of 10,000 CHD patients (50 years of age or older) with any abnormal lipid parameter (LDL-C, HDL-C, Non-HDL-C, and/or TG). The expected number of CHD events was calculated using the Framingham Heart Study equation for secondary prevention. Age, sex, and coronary risk-factor data for patients with CHD were obtained from a nationally-representative US health survey. Direct medical costs were expressed in $US 2006, discounted annually at 3%. The drugs of interest included simvastatin (S) alone and fixed-dose extended release niacin/simvastatin (ERN/S), allowing an evaluation of increasing doses of S or adding a second agent to S. RESULTS: Direct medical costs of CHD events over 5 years are estimated to be approximately $3436 per patient for patients treated with 20 mg of S. These costs would decrease by 8.8% with 1000/20 mg of ERN/S. Compared to more aggressive lipid therapy with 40 mg of S, 1000/40 mg of ERN/S would decrease CHD costs by 9.1%. Relative to a maximum dose of 80 mg of S, the maximum dose of ERN/S (2000/40 mg) would reduce CHD event costs by 11.2%. CONCLUSION: Intensifying lipid-modifying therapy with fixed-dose ERN/S combinations would further reduce direct medical costs of CHD events more effectively than S monotherapy in a secondary prevention population. Further research on the cost-effectiveness of intensifying dyslipidemia treatment is warranted.