poorly neutralizing crossreactive antibodies against the fusion loop of west nile virus envelope protein protect in vivo via fcgamma receptor and complementdependent effector mechanisms the human antibody response to flavivirus infection is dominantly directed against a crossreactive epitope on the fusion loop of domain ii diifl of the envelope e protein although antibodies against this epitope fail to recognize fully mature west nile virus wnv virions and accordingly neutralize infection poorly in vitro their functional properties in vivo remain less well understood here we show that while passive transfer of poorly neutralizing monoclonal antibodies mab and polyclonal antibodies against the diifl epitope protect against lethal wnv infection in wildtype mice they fail to protect mice lacking activating fc receptors fcr and the complement opsonin c1q consistent with this an aglycosyl chimeric mousehuman diifl mab e28 variant that lacks the ability to engage fcr and c1q also did not protect against wnv infection in wildtype mice using a series of immunodeficient mice and antibody depletions of individual immune cell populations we demonstrate that the nonneutralizing diifl mab e28 does not require t b or nk cells inflammatory monocytes or neutrophils for protection rather e28 treatment decreased viral load in the serum early in the course of infection which resulted in blunted dissemination to the brain an effect that required phagocytic cells c1q and fcriii cd16 overall these studies enhance our understanding of the functional significance of immunodominant poorly neutralizing antibodies in the polyclonal human antiflavivirus response and highlight the limitations of current in vitro surrogate markers of protection such as cellbased neutralization assays which cannot account for the beneficial effects conferred by these antibodies