The role of the collagen receptor glycoprotein VI (GPVI) in arteriolar thrombus formation was studied in FcRγ-null mice (FcRγ^–/–) lacking platelet surface GPVI. Thrombi were induced with severe or mild FeCl₃ injury. Collagen exposure was significantly delayed and diminished in mild compared with severe FeCl₃ injury. Times to initial thrombus formation and vessel occlusion were delayed in FcRγ^–/– compared with wild-type mice after severe injury. Platelet accumulation in wild-type mice was decreased after mild compared with severe injury. However, there was little difference between platelet accumulation after severe or mild injury in FcRγ^–/–. These data indicate a significant role for GPVI in FeCl₃-induced thrombus formation. Pretreatment of wild-type mice with lepirudin further impaired mild FeCl₃-induced thrombus formation, demonstrating a role for thrombin. Laser-induced thrombus formation in wild-type and FcRγ^–/– was comparable. Collagen exposure to circulating blood was undetectable after laser injury. Normalized for thrombus size, thrombus-associated tissue factor was 5-fold higher in laser-induced thrombi than in severe FeCl₃-induced thrombi. Thus, platelet activation by thrombin appears to be more important after laser injury than platelet activation by GPVI-collagen. It may thus be important when considering targets for antithrombotic therapy to use multiple animal models with diverse pathways to thrombus formation.