Abstract Interaction between target cell CD47 and the inhibitory macrophage receptor signal regulatory protein α (SIRPα) counteracts macrophage phagocytosis of CD47-expressing host cells. As platelets also express CD47, we asked whether inhibitory CD47/SIRPα signaling regulates normal platelet turnover and clearance of platelets in immune thrombocytopenic purpura (ITP). CD47-/- mice had a mild spontaneous thrombocytopenia, which was not due to a decreased platelet half-life as a result of increased expression of P-selectin, CD61, or phosphatidylserine. In contrast, CD47-/- platelets were rapidly cleared when transfused into CD47+/+ recipients, whereas CD47+/- platelets had a nearly normal half-life in CD47+/+ mice under nonautoimmune conditions. CD47-/- mice were more sensitive to ITP, as compared with CD47+/+ mice. In vitro, macrophage phagocytosis of immunoglobulin G (IgG)–opsonized CD47-/- platelets was significantly higher than that for equally opsonized CD47+/+ platelets. However, when SIRPα was blocked, phagocytosis of CD47+/+ platelets increased to the level of CD47-/- platelets. Phagocytosis of opsonized CD47+/- platelets was higher than that for CD47+/+ platelets, but lower than that for CD47-/- platelets, suggesting a gene-dose effect of CD47 in this system. In conclusion, we suggest that inhibitory CD47/SIRPα signaling is involved in regulating platelet phagocytosis in ITP, and that targeting SIRPα may be a new means of reducing platelet clearance in ITP.