Our experiments are consistent with a model in which the therapeutic efficacy of monoclonal antibodies is determined by properties in addition to neutralization: (i) the monoclonal antibody (E24) with the strongest neutralizing activity in vitro did not have the greatest efficacy in vivo; (ii) an aglycosyl version of E16 that lacked the ability to fix complement or bind to Fc γ receptors had equivalent neutralizing but reduced therapeutic activity; (iii) E16 was less potent in mice that lacked Fc γ receptors. E16 was humanized as a possible therapeutic measure for humans. Hm-E16 bound DIII with similar affinity and showed efficacy as postexposure therapy. Moreover, it may be possible to improve Hm-E16 by a b c introducing mutations that enhance affinity, creating forms of E16 that more readily cross the blood-brain barrier, and combining monoclonal antibodies that neutralize WNV infection through independent mechanisms. Our results are the first successful demonstration of a humanized monoclonal antibody as postexposure therapy against a viral disease, and suggest that antibody-based therapeutics may have more broad utility than previously appreciated, especially in the treatment of CNS infections in which an effective antibody response is important for limiting virus dissemination and injury to neurons.