Mosquitoes infect human beings with arboviruses while taking a blood meal, inoculating virus with their saliva. Mosquito saliva contains compounds that counter host hemostatic, inflammatory, and immune responses. Modulation of these crucial defensive responses may facilitate virus infection. Using a murine model we explored the potential for mosquitoes to impact the course of West Nile virus (WNV) disease by determining whether differences in pathogenesis occurred in the presence or absence of mosquito saliva. Mice inoculated intradermally with 10(4) pfu of WNV subsequent to the feeding of mosquitoes developed more progressive infection, higher viremia, and accelerated neuroinvasion than the mice inoculated with WNV alone. At a lower dose of WNV (10(2) pfu), mice fed upon by mosquitoes had a lower survival rate. This study suggests that mosquito feeding and factors in mosquito saliva can potentiate WNV infection, and offers a possible mechanism for this effect via accelerated infection of the brain.