We performed an analysis of the cost-effectiveness of treating individuals with significantly elevated levels of total serum cholesterol (greater than 6.85 mmol/L [greater than 265 mg/dL], comparing treatment with three alternative agents: cholestyramine resin, colestipol, and oat bran (a soluble fiber). We simulated a program for lowering cholesterol levels that was similar to that of the Coronary Primary Prevention Trial, and then used the outcomes of the trial to calculate the incremental cost per year of life saved (YOLS) from the perspective of society. Our findings suggest that the cost per YOLS ranges from $117,400 (cholestyramine resin packets) to $70,900 (colestipol packets) and $17,800 (oat bran). Using bulk drug reduces the cost per YOLS to $65,100 (cholestyramine resin) and $63,900 (colestipol). Targeting bulk colestipol treatment only to smokers has a cost per YOLS of $47,010; the incremental cost of treating nonsmokers would be $89,600 per additional YOLS. Although pharmacologic therapy has substantial costs, it may be more cost-effective when low-cost forms are applied to particular high-risk groups, such as smokers. However, a broad public health approach to lowered cholesterol levels by additional dietary modification, such as with soluble fiber, may be preferred to a medically oriented campaign that focuses on drug therapy.