Antiplatelet therapy, most notably aspirin, has been well documented to reduce risks of subsequent cardiovascular disease (CVD) in secondary prevention, acute myocardial infarction (MI), acute occlusive stroke, as well as in primary prevention. In secondary prevention, the most recent Antithrombotic Trialists' Collaboration reviewed 194 published randomized trials of antiplatelet therapy, mostly aspirin, involving more than 212 000 patients (ie, 135 000 using antiplatelet therapy or control and 77 000 using different antiplatelet regimens). In a very wide range of patients who have survived a prior occlusive vascular event-including MI, transient ischemic attacks, occlusive stroke, unstable and stable angina, percutaneous coronary interventions, and coronary artery bypass graft-aspirin prevents about 25% of serious vascular events. Among patients suffering acute Ml or acute occlusive stroke, aspirin begun promptly and continued long-term reduces risks of subsequent MI, stroke, and vascular death. In acute coronary syndromes, clopidogrel added to aspirin further reduces the risk of important vascular events, but not mortality, and causes more side effects, especially bleeding. For patients undergoing percutaneous coronary interventions, the addition of a short-term infusion of a glycoprotein IIb/IIIa receptor antagonist to aspirin prevents additional vascular events during the early in-hospital period but also increases the risk of major bleeding. Ongoing research is investigating other combinations of different antiplatelet drugs. In all these high-risk patients, there is a small excess of major bleeding among those assigned at random to aspirin, which is far outweighed by the magnitude of benefits on CVD. During an acute MI, after a loading dose of 160 mg to 325 mg aspirin, daily doses ranging from 75 to 150 mg daily are as effective as higher doses. For long-term treatment, the effects of doses < 75 mg daily are less certain. Although side effects are dose-related, especially in doses > 325 mg daily, no antiplatelet regimen is more effective than aspirin for long-term use. In primary prevention, 5 randomized trials have been published involving more than 60 000 apparently healthy men and women. Persons randomized to receive aspirin in these trials had significant reductions in risk of a first MI (32%) and important vascular events (15%). Since the numbers of strokes and vascular deaths were insufficient to distinguish between the benefits found in secondary prevention and no effect, use of aspirin in primary prevention should be weighed in light of the cardiovascular risk profile, the side effects of the drug, and its clear benefit in reducing risk of a first MI. Aspirin should be an adjunct, not an alternative, to managing other cardiovascular risk factors. Recently, the US Preventive Services Task Force and the American Heart Association recommended aspirin use for all men and women whose 10-year risks are > 6% and > or = 10%, respectively. In all these patient categories, including secondary prevention, acute MI and acute occlusive stroke, as well as primary prevention, increased and appropriate use of aspirin will prevent large numbers of premature deaths and MIs.