West Nile (WN) virus causes fatal meningoencephalitis in laboratory mice, and γδ T cells are involved in the protective immune response against viral challenge. We have now examined whether γδ T cells contribute to the development of adaptive immune responses that help control WN virus infection. Approximately 15% of TCRδ−/− mice survived primary infection with WN virus compared with 80–85% of the wild-type mice. These mice were more susceptible to secondary challenge with WN virus than the wild-type mice that survived primary challenge with the virus. Depletion of γδ T cells in wild-type mice that survived the primary infection, however, does not affect host susceptibility during secondary challenge with WN virus. Furthermore, γδ T cells do not influence the development of Ab responses during primary and at the early stages of secondary infection with WN virus. Adoptive transfer of CD8+ T cells from wild-type mice that survived primary infection with WN virus to naive mice afforded partial protection from lethal infection. In contrast, transfer of CD8+ T cells from TCRδ−/− mice that survived primary challenge with WN virus failed to alter infection in naive mice. This difference in survival correlated with the numeric and functional reduction of CD8 memory T cells in these mice. These data demonstrate that γδ T cells directly link innate and adaptive immunity during WN virus infection.