This study estimated the cost-effectiveness of the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors available in Canada for the primary prevention of coronary heart disease (CHD). A model of the cost-effectiveness of therapy used to modify low-density lipoprotein (LDL) cholesterol and high-density lipoprotein cholesterol levels was developed in the primary prevention of CHD based on risk functions from the Framingham Heart Study and Canadian data on coronary risk factors and the cost of treating the leading manifestations of CHD. Relative to no treatment, discounted gains in life expectancy range from 0.174 year for fluvastatin 40 mg to 0.215 year for simvastatin 10 mg. Costs per year-of-life-saved range from $38,800 for fluvastatin 40 mg to $56,200 for pravastatin 20 mg. In the incremental analysis relative to fluvastatin 40 mg, additional gains in life expectancy range from 0.011 year for pravastatin 20 mg to 0.041 year for simvastatin 10 mg, and incremental cost-effectiveness ratios range from $88,200 for simvastatin, 10 mg to $330,300 for pravastatin 20 mg. Our analysis showed that the cost-effectiveness of cholesterol-lowering therapy is sensitive to pretreatment risk of CHD, as expressed by pretreatment cholesterol levels and the presence of additional risk factors such as hypertension, diabetes, and smoking. The results of the analysis suggest that it is more cost-effective to initiate treatment with fluvastatin than with pravastatin, simvastatin, or lovastatin. Sensitivity analysis showed the results to be stable even if the lipid-lowering effect of fluvastatin is varied by 23% from the original assumption of 25% LDL reduction (ie, from 19.3% to 30.8%). Limitations of the study are recognized and discussed. A head-to-head comparison of these HMG-CoA reductase inhibitors could provide further evidence that therapy initiated with fluvastatin may be the most cost-effective way to treat patients with hypercholesterolemia who are eligible for treatment with HMG-CoA reductase inhibitors.