Integrin-mediated platelet function plays an important role in primary hemostasis. Growth-differentiation factor 15 (GDF-15) has been shown to inhibit β(2) -integrin activation in leukocytes. We investigated the effect of GDF-15 on platelet integrin activation in vitro and in different in vivo models of thrombus formation. GDF-15(-/-) mice showed an accelerated thrombus formation and a reduced survival rate after collagen-induced pulmonary thromboembolism. In reconstitution experiments, recombinant GDF-15 decelerated thrombus formation and prolonged the bleeding time. In vitro experiments demonstrated that GDF-15 pretreated, agonist-stimulated platelets showed decreased binding to fibrinogen in flow chamber assays and reduced activation of β(1) - and β(3) -integrins in flow cytometry experiments. Pretreating human and mouse platelets with GDF-15 reduced platelet aggregation. Mechanistically, GDF-15 prevents agonist-induced Rap1- dependent α(II) (b) β(3) activation by activating PKA. Platelet P-selectin expression and dense granule secretion after stimulation were unaffected by GDF-15, indicating a specific effect of GDF-15 on integrin activation. GDF-15 specifically inhibits platelet integrin activation. These findings may have profound clinical implications for the treatment of hemostatic conditions involving platelets.