Patients with diabetes mellitus (DM) have accelerated atherothrombotic disease of coronary, cerebral, leg, and other vessels. The major cause of death is cardiovascular, and the risk for a myocardial infarction (MI) in a patient with DM who has never had a MI is the same as a nondiabetic individual who has already had one. In this paper, we review the major reasons for a prothrombotic state in patients with DM: alterations in the intrinsic coagulation and fibrinolytic systems and many abnormalities of platelet function. Increased platelet thromboxane production as well as activation of platelet receptors for fibrinogen and or adenosine diphosphate (ADP) are often present, and can be treated with aspirin (acetylsalicylic acid) and/or receptor blockers. Review of the major primary prevention trials in DM indicates that a significantly reduced risk for MI or major cardiovascular events may be obtained by enteric-coated aspirin, 81-325 mg/day. There is emerging consensus that this is recommended strategy in adult (aged >30 years) patients with DM who are at high vascular risk. Surveys suggest that this includes virtually every patient with type 2 DM in the US, as well as many patients with complicated type 1 DM. These recommendations are also appropriate for secondary prevention. Data supporting the use of clopidogrel as an alternative drug in the case of aspirin allergy or other contraindications are reviewed. Evidence is presented in support of using aspirin plus clopidogrel in acute coronary syndromes (ACS), and a meta-analysis of six trials of platelet glycoprotein (GP) IIb/IIIa inhibitors and aspirin in diabetic patients with ACS establishes this regimen as an effective choice. Although bleeding episodes are more common with combined antiplatelet therapy for ACS than for aspirin alone, the benefit of a significant reduction in 30-day mortality appears to outweigh the risk of major bleeding. It is concluded that major advances in our understanding of the prothrombotic state in DM have been made. Evidence from controlled clinical trials supports the use of enteric-coated aspirin, 81-325 mg/day, as a primary and a secondary prevention strategy in adults with DM with high vascular risk. In ACS, combination therapy with aspirin plus clopidogrel or alternatively, aspirin plus a platelet GP IIb/IIIa inhibitor is supported by prospective trial data. These approaches should be added to the other multifactorial preventive strategies directed at lowering the risk for major vascular events in patients with DM.