We reviewed the efficacy and safety of combination antithrombotic therapy with aspirin plus warfarin versus aspirin alone in patients with atherosclerotic heart disease. We performed a comprehensive MEDLINE search of English-language reports published between 1966 and 2002 and search of references and relevant papers. Only clinical research studies on primary or secondary prevention of cardiovascular events in patients at high risk for coronary artery disease or patients experiencing unstable angina or myocardial infarction were included. Despite daily aspirin treatment, many patients break through aspirin treatment and experience cardiovascular events. Individuals at high risk for coronary disease or with established disease benefit from combination therapy with aspirin plus warfarin, if compliance with warfarin is greater than 70% and the target international normalized ratio (INR) of 2.0-2.5 is achieved. Combination therapy within these parameters leads to a 29-45% reduction in the risk of death, reinfarction and/or ischemic stroke. There is a significant increase in the rate of minor and a slight increase in the rate of major bleeding with combination therapy. Other potential indications for combination therapy include myocardial infarction associated with acute left ventricular aneurysm or significant left ventricular systolic dysfunction. In spite of reluctance to use oral anticoagulants, several large, randomized clinical trials support combination therapy with aspirin plus warfarin (INR, 2.0-2.5) in high-risk patients with atherosclerotic heart disease. Combination therapy increases the risk of minor and major bleeding, but not intracranial bleeding.