IFNγ drives antiparasite responses and immunopathology during infection with Plasmodium species. Immunity-related GTPases (IRGs) are a class of IFNγ-dependent proteins that are essential for cell autonomous immunity to numerous intracellular pathogens. However, it is currently unknown whether IRGs modulate responses during malaria. We have used the Plasmodium berghei ANKA (PbA) model, in which mice develop experimental cerebral malaria (ECM), to study the roles of IRGM1 and IRGM3 in immunopathology. Induction of mRNA for Irgm1 and Irgm3 was found in the brains and spleens of infected mice at times of peak IFNγ production. Irgm3-/-, but not Irgm1-/-mice, were completely protected from the development of ECM, and this protection was associated with decreased induction of inflammatory cytokines, as well as decreased recruitment and activation of CD8+ T cells within the brain. To investigate the impact of Irgm3-deficiency on CD8+ cell differentiation during PbA infection, parasite specific CD8+ cells were adoptively transferred into wild-type or Irgm3-/- hosts. Although antigen-specific proliferation of transferred CD8+ T cells was not diminished compared to WT recipients following PbA infection, T cells transferred into Irgm3-/- recipients showed a striking impairment of effector differentiation. Decreased induction of several inflammatory cytokines and chemokines (IL-6, CCL2, CCL4, CCL4), as well as enhanced mRNA expression of type-I IFNs were found in the spleens of Irgm3-/- mice at day 4 post-infection. Furthermore, diminished induction of CD86 expression by plasmacytoid DC was seen in Irgm3-/- mice. Together, these data suggest that protection from ECM pathology in Irgm3-/- mice occurs due to impaired generation of CD8+ effector function. This defect is non-intrinsic to CD8+ T cells. Instead, diminished T cell responses most likely result from defective initiation of inflammatory responses in myeloid cells.