Myeloid differentiation factor 88 (MyD88) is an essential adaptor protein in the Toll-like receptor-mediated innate signaling pathway, as well as in interleukin-1 receptor (IL-1R) and IL-18R signaling. The importance of MyD88 in the regulation of innate immunity to microbial pathogens has been well demonstrated. However, its role in regulating acquired immunity to viral pathogens and neuropathogenesis is not entirely clear. In the present study, we examine the role of MyD88 in the CD4(+) T-cell response following lymphocytic choriomeningitis virus (LCMV) infection. We demonstrate that wild-type (WT) mice developed a CD4(+) T-cell-mediated wasting disease after intracranial infection with LCMV. In contrast, MyD88 knockout (KO) mice did not develop wasting disease in response to the same infection. This effect was not the result of MyD88 regulation of IL-1 or IL-18 responses since IL-1R1 KO and IL-18R KO mice were not protected from weight loss. In the absence of MyD88, naive CD4(+) T cells failed to differentiate to LCMV-specific CD4 T cells. We demonstrated that MyD88 KO antigen-presenting cells are capable of activating WT CD4(+) T cells. Importantly, when MyD88 KO CD4(+) T cells were reconstituted with an MyD88-expressing lentivirus, the rescued CD4(+) T cells were able to respond to LCMV infection and support IgG2a antibody production. Overall, these studies reveal a previously unknown role of MyD88-dependent signaling in CD4(+) T cells in the regulation of the virus-specific CD4(+) T-cell response and in viral infection-induced immunopathology in the central nervous system.