Background: Both aspirin and clopidogrel reduce the rate of cardiovascular events in patients with coronary heart disease. We estimated the cost effectiveness of the increased use of aspirin, clopidogrel, or both for secondary prevention in patients with coronary heart disease. Methods: We used the Coronary Heart Disease Policy Model, a computer simulation of the U.S. population, to estimate the incremental cost effectiveness (in dollars per quality-adjusted years of life gained) of four strategies in patients over 35 years of age with coronary disease from 2003 to 2027: aspirin for all eligible patients (i.e., those who were not allergic to or intolerant of aspirin), aspirin for all eligible patients plus clopidogrel for patients who were ineligible for aspirin, clopidogrel for all patients, and the combination of aspirin for all eligible patients plus clopidogrel for all patients. Results: The extension of aspirin therapy from the current levels of use to all eligible patients for 25 years would have an estimated cost-effectiveness ratio of about $11,000 per quality-adjusted year of life gained. The addition of clopidogrel for the 5 percent of patients who are ineligible for aspirin would cost about $31,000 per quality-adjusted year of life gained. Clopidogrel alone in all patients or in routine combination with aspirin had an incremental cost of more than $130,000 per quality-adjusted year of life gained and remained financially unattractive across a wide range of assumptions. However, clopidogrel alone or in combination with aspirin would cost less than $50,000 per quality-adjusted year of life gained if its price were reduced by 70 to 82 percent, to $1.00 and $0.60 per day, respectively. Conclusions: Increased prescription of aspirin for secondary prevention of coronary heart disease is attractive from a cost-effectiveness perspective. Because clopidogrel is more costly, its incremental cost effectiveness is currently unattractive, unless its use is restricted to patients who are ineligible for aspirin.