Platelet activation plays a central role in hemostasis and thrombosis. Many platelet agonists function through G-protein–coupled receptors. Epinephrine activates the α_2A-adrenergic receptor (α_2A) that couples to G_z in platelets. Although α_2A was originally cloned from platelets, its role in thrombosis and hemostasis is still unclear. Through analysis of α_2A-deficient mice, variable tail bleeding times were observed. In vitro, epinephrine potentiated activation/aggregation responses of wild-type but not α_2A-deficient platelets as determined by flow cytometry and aggregometry, whereas perfusion studies showed no differences in platelet adhesion and thrombus formation on collagen. To test the in vivo relevance of α_2A deficiency, mice were subjected to 3 different thrombosis models. As expected, α_2A-deficient mice were largely protected from lethal pulmonary thromboembolism induced by the infusion of collagen/epinephrine. In a model of FeCl₃-induced injury in mesenteric arterioles, α_2A^–/– mice displayed a 2-fold increase in embolus formation, suggesting thrombus instability. In a third model, the aorta was mechanically injured, and blood flow was measured with an ultrasonic flow probe. In wild-type mice, all vessels occluded irreversibly, whereas in 24% of α_2A-deficient mice, the initially formed thrombi embolized and blood flow was reestablished. These results demonstrate that α_2A plays a significant role in thrombus stabilization.