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Significance Novel therapies are urgently needed that can ameliorate the clinical syndromes of cerebral malaria, the most severe consequences of Plasmodium infection, and thereby reduce malaria fatality. Monoclonal antibodies that target CD47, a “don’t eat me” signal, have been demonstrated to enhance cellular clearance of cancer cells by promoting macrophage phagocytosis. We sought to adopt this therapeutic strategy to ameliorate the clinical syndromes associated with cerebral malaria with the goals of reducing disease-associated morbidity and mortality. We demonstrate that CD47 blockade by anti-CD47 injection leads to survival from cerebral malaria in mice., CD47 is an antiphagocytic “don’t eat me” signal that inhibits programmed cell removal of self. As red blood cells (RBCs) age they lose CD47 expression and become susceptible to programmed cell removal by macrophages. CD47−/− mice infected with Plasmodium yoelii, which exhibits an age-based preference for young RBCs, were previously demonstrated to be highly resistant to malaria infection. Our study sought to test the therapeutic benefit of CD47 blockade on ameliorating the clinical syndromes of experimental cerebral malaria (ECM), using the Plasmodium berghei ANKA (Pb-A) murine model. In vitro we tested the effect of anti-CD47 mAb on Plasmodium-infected RBC phagocytosis and found that anti-CD47 treatment significantly increased clearance of Plasmodium-infected RBCs. Infection of C57BL/6 mice with Pb-A is lethal and mice succumb to the clinical syndromes of CM between days 6 and 10 postinfection. Strikingly, treatment with anti-CD47 resulted in increased survival during the cerebral phase of Pb-A infection. Anti-CD47–treated mice had increased lymphocyte counts in the peripheral blood and increased circulating levels of IFN-γ, TNF-α, and IL-22. Despite increased circulating levels of inflammatory cytokines, anti-CD47–treated mice had reduced pathological features in the brain. Survival of ECM in anti-CD47–treated mice was correlated with reduced cellular accumulation in the cerebral vasculature, improved blood–brain barrier integrity, and reduced cytotoxic activity of infiltrating CD8+ T cells. These results demonstrate the therapeutic benefit of anti-CD47 to reduce morbidity in a lethal model of ECM, which may have implications for preventing mortality in young African children who are the highest casualties of CM.