1. Prospective and interventional studies demonstrate an inverse relationship between plasma high-density lipoprotein (HDL)-cholesterol and the incidence of coronary artery disease. Although the atheroprotective effects of HDL are usually attributed to the reverse cholesterol transport, in which HDL shuttles cholesterol from cells in the arterial wall to the liver, other mechanisms are also under investigation. 2. Platelets are involved in both the initiation and progression of atherosclerotic lesions. In addition, the formation of thrombi over ruptured atherosclerotic plaques results in the narrowing or complete occlusion of coronary arteries. Current experimental evidence suggests that HDL may exert antiplatelet effects and thereby counteract the development of atherothrombotic vascular disease. 3. In vitro studies show that HDL inhibits agonist-stimulated platelet aggregation, fibrinogen binding, granule secretion and liberation of thromboxane A(2). Inhibitory effects of HDL are mediated, in part, by scavenger receptor type B1 and/or the apolipoprotein E receptor apoER2/LRP8 and are linked to the induction of intracellular signalling cascades encompassing stimulation of protein kinase C, cytoplasmatic alkalization and generation of nitric oxide. 4. Populational studies demonstrate that there is an inverse association between plasma HDL levels and recurrent venous thromboembolism. In addition, HDL-cholesterol has been identified as an independent predictor of acute platelet thrombus formation. The administration of reconstituted HDL particles in humans attenuates ex vivo platelet activation. 5. The present review summarizes recent advances in understanding HDL-platelet interactions and discusses the potential use of HDL-like particles in the therapy of thrombosis.