The recent observation that knock-out of protease-activated receptor-4 (PAR4) ablates thrombin signaling in mouse platelets and protects against ferric chloride–induced thrombosis of mouse mesenteric arterioles suggests that thrombin's actions on platelets can play an important role in thrombosis. Complete ablation of thrombin signaling would be difficult to achieve in human beings because human platelets have 2 thrombin receptors that are each capable of mediating transmembrane signaling. However, it is possible that complete ablation of thrombin signaling in platelets is not necessary for an antithrombotic effect. In mouse platelets, PAR3 functions as a cofactor that binds thrombin and promotes productive cleavage of PAR4, and thrombin responses are decreased but not absent inPar3^−/− platelets. We now report thatPar3^−/− mice were protected against ferric chloride–induced thrombosis of mesenteric arterioles and against thromboplastin-induced pulmonary embolism. Surprisingly,Par3^−/− and Par4^−/−mice showed similar degrees of protection in these models and similar prolongation of tail bleeding times. Thus, even a partial decrease in mouse platelet responsiveness to thrombin protected against thrombosis and impaired hemostasis in some settings. These results demonstrate the importance of PAR3's unusual cofactor function and underscore the relative importance of thrombin's actions on platelets in vivo. They also suggest that PAR inhibition might be explored for the prevention or treatment of thrombosis in human beings.