Death-associated protein kinase-related apoptosis-inducing kinase-2 (Drak2), a member of the death-associated protein family of serine/threonine kinases, is specifically expressed in T and B cells. In the absence of Drak2, mice are resistant to experimental autoimmune encephalomyelitis due to a decrease in the number of cells infiltrating the CNS. In the present study, we investigated the role of Drak2 in West Nile virus (WNV)-induced encephalitis and found that Drak2(-/-) mice were also more resistant to lethal WNV infection than wild-type mice. Although Drak2(-/-) mice had an increase in the number of IFN-gamma-producing T cells in the spleen after infection, viral levels in the peripheral tissues were not significantly different between these two groups of mice. In contrast, there was a reduced viral load in the brains of Drak2(-/-) mice, which was accompanied by a decrease in the number of Drak2(-/-) CD4(+) and CD8(+) T cells in the brain following WNV infection. Moreover, we detected viral Ags in T cells isolated from the spleen or brain of WNV-infected mice. These results suggest that following a systemic infection, WNV might cross the blood brain barrier and enter the CNS by being carried by infected infiltrating T cells.