Transgenic mouse lines were created that express FcγRIIA on platelets and macrophages at human physiologic levels, and they were used to explore the consequences in vivo of activating antiplatelet antibodies. Anti-CD9 antibody activated platelets of FcγRIIA transgenic (tg) mice and, following injection in vivo, caused more rapid severe thrombocytopenia than nonactivating antiplatelet antibody. Anti-CD9 injected into FcγRIIA tg crossed with FcR γ-chain knockout (γ-KO) mice caused thrombosis and shock in all mice, and death in 16 of 18 mice. The shock depended on platelet Fc receptor density and antibody dose. On histologic examination, the lung vasculature of anti-CD9–treated FcγRIIA tg × γ-KO mice contained extensive platelet-fibrin thrombi. Thrombosis and shock in FcγRIIA tg mice in the context of the FcR γ-chain knockout suggested the importance of the interplay of intravascular platelet activation and splenic clearance. Reduction of splenic clearance surgically (splenectomy) or functionally (monoclonal antibody treatment) also facilitated anti-CD9–mediated shock in FcγRIIA tg mice. The spleen, which clears nonactivating antibody-coated platelets leading to thrombocytopenia, appears to play a protective role in the thrombosis and shock observed with activating antiplatelet antibody. The data indicate that antibodies, which activate platelets in an FcγRIIA-dependent manner, can lead to thrombosis, shock, and death. Furthermore, antibody titer, platelet Fc receptor density, and splenic clearance are likely important determinants of the outcome.