MyD88 is a key adaptor molecule in innate resistance, engaged in most Toll-like receptor, as well as IL-1 and IL-18, signalling. Here, we analyzed the role of MyD88 in innate resistance during infection with vesicular stomatitis virus (VSV) using myd88–/– mice. We found an increased susceptibility to VSV in myd88–/– mice, which was not explained by reduced type I IFN or neutralizing antibody responses. Susceptibility of myd88–/– mice correlated with impaired recruitment of immune cells to the site of infection. In the absence of MyD88 signalling, VSV rapidly spread to the spinal cord and brain causing lethal encephalitis.