West Nile (WN) virus causes fatal meningoencephalitis in laboratory mice, thereby partially mimicking human disease. Using this model, we have demonstrated that mice deficient in γδ T cells are more susceptible to WN virus infection. TCRδ−/− mice have elevated viral loads and greater dissemination of the pathogen to the CNS. In wild-type mice, γδ T cells expanded significantly during WN virus infection, produced IFN-γ in ex vivo assays, and enhanced perforin expression by splenic T cells. Adoptive transfer of γδ T cells to TCRδ−/− mice reduced the susceptibility of these mice to WN virus, and this effect was primarily due to IFN-γ-producing γδ T cells. These data demonstrate a distinct role for γδ T cells in the control of and prevention of mortality from murine WN virus infection.