Although the interactions of complement and viruses have been widely studied, the function of C5 and the membrane attack complex in the context of viral infection or antibody-mediated neutralization remains controversial. Using C5-depleted or -deficient human or mouse sera, we show that C5 does not contribute to the antibody-dependent or -independent neutralization of West Nile virus (WNV) in cell culture. Consistent with this, C5 neither contributed to protection against WNV pathogenesis nor augmented the neutralizing efficacy of complement-fixing anti-WNV neutralizing antibodies in mice. Although previous studies established that activation of the classical, lectin, and alternative complement pathways restricts WNV infection, our results show little effect of C5 and by inference the terminal lytic complement components. Overall, these results enhance our mechanistic understanding of how complement controls flavivirus infections.