Pharmacotherapies to lower blood pressure and cholesterol are effective in the primary prevention of cardiovascular disease (CVD). The use of fixed-dose medication combinations has not been well studied. The authors created a Markov model to analyze the cost-effectiveness of 4 fixed-dose medications for primary CVD prevention in men. The initial decision node was to treat or not treat men older than 55 years, without CVD, hypertension, or dyslipidemia with a combination of simvastatin, captopril, hydrochlorothiazide, and atenolol. Probability, costs, and effectiveness were derived from the literature. The outcome variable was marginal cost per quality-adjusted life-year (QALY). Sensitivity analyses were performed. The average cost of treatment was $70,000 compared with $93,000 for non-treatment. Treatment resulted in 13.62 QALYs vs 12.96 QALYs without treatment. Primary prevention of CVD with fixed-dose medications dominated "no-treatment." The use of a fixed-dose polypharmacy approach to CVD prevention in men older than 55 years may be cost-effective.