Stroke is the third most common cause of adult mortality in the United States. Antithrombotic agents form the mainstay of stroke preventive therapy. Aspirin produces a modest reduction in the risk of secondary stroke and is widely recommended for initial administration. The thienopyridines, ticlopidine and clopidogrel, are useful alternatives for secondary stroke prevention in patients who do not respond to or cannot take aspirin. They have not been proven more clinically effective than aspirin and have been associated with thrombotic thrombocytopenic purpura. The combination of aspirin and ER-dipyridamole offers multiple mechanisms of action and an additive effect on stroke risk reduction compared with either agent alone. A twofold increase in risk reduction and a favorable safety profile suggest that the combination can be used as a first-line agent in a prophylactic regimen for secondary stroke.