Dendritic cells are the most potent antigen-presenting cells, but their roles in blood-stage malaria infection are not fully understood. We examined the effects of Flt3 ligand, a cytokine that induces dendritic cell production, in vivo on the course of infection with Plasmodium berghei ANKA. Mice treated with Flt3 ligand showed preferential expansion of CD8(+) dendritic cells and granulocytes, as well as lower levels of parasitemia, and were protected from the development of lethal experimental cerebral malaria (ECM). Rag2 knockout mice treated with Flt3 ligand also showed inhibition of parasitemia, suggesting that this protection was due, at least in part, to the stimulation of innate immunity. However, it was unlikely that the inhibition of ECM was due simply to the reduction in the level of parasitemia. In the peripheral T cell compartment, CD8(+) T cell levels were markedly increased in Flt3 ligand-treated mice after infection. These CD8(+) T cells expressed CD11c and upregulated CXCR3, while the expression of CD137, CD25, and granzyme B was reduced. In the brain, the number of sequestered CD8(+) T cells was not significantly different for treated versus untreated mice, while the proportion of CD8(+) T cells that produce gamma interferon (IFN-γ) and granzyme B was significantly reduced in treated mice. In addition, sequestration of parasitized red blood cells (RBCs) in the brain was reduced, suggesting that altered CD8(+) T cell activation and reduced sequestration of parasitized RBCs culminated in inhibition of ECM development. These results suggest that the quantitative and qualitative changes in the dendritic cell compartment are important for the pathogenesis of ECM.