CD47 is an anti-phagocytic (don’t eat me) signal that inhibits programmed cell removal of self and loss of this molecule by aging erythrocytes is associated with increased susceptibility to clearance by macrophages. We have investigated the role of CD47 in malaria immunity and pathogenesis in murine malaria models. Previously, we demonstrated that absence of CD47 confers resistance to infection with Plasmodium yoelii 17XNL, a murine malaria that exhibits an aged-based preference for young erythrocytes. Next, we established that CD47 blockade with an anti-CD47 monoclonal antibody promotes survival and reduces the pathologic features of cerebral malaria during Plasmodium berghei ANKA (Pb−A) infection in C57BL/6 mice, a murine model of experimental cerebral malaria (ECM). To delineate the immunological mechanism of CD47 regulation of ECM pathogenesis, we present studies comparing Pb−Ainfection in wildtype (WT) versus CD47 KO C57BL/6 mice. In CD47 KO mice, absence of CD47 resulted in partial but highly significant (p<0.001, log-rank) resistance to ECM; following infection with Pb−A parasites, 22/23 (95.6%) WT mice developed ECM by day 10 post-infection. In contrast, only 13/23 (56.5%) of CD47 KO mice succumbed to malaria during the cerebral phase of infection. Through flow cytometric analysis of brain sequestered and splenic immune cell subsets and cytokine profiling of serum, we show that absence of CD47 during Pb−A malaria is associated with a significant reduction in brain sequestered CD8+ T cells which are pathogenic during ECM and alteration of a small subset of cytokines. In addition, comparative analysis of WT versus CD47 KO brain tissue by immunohistology demarcates clear differences in pathologic features such as hypertrophied endothelial cells, presence of parasite hemozoin, macrophage infiltration, vascular lesions, and ring hemorrhages. A further understanding of the mechanism of anti-CD47 antibody-mediated protection from ECM may open avenues for novel immunologic-based treatment options against cerebral malaria in African children.