Abstract: The present invention relates to anti-West Nile virus E protein (WNE) antibodies, including human antibodies, and antigen-binding portions thereof. In particular, the invention relates to such antibodies and portions that prevent, inhibit, or treat a flavivirus infection, including a West Nile Virus infection. The invention also relates to antibodies that are chimeric, bispecific, derivatized, single chain antibodies or that are portions of fusion proteins. The invention also relates to isolated heavy and light chain immunoglobulins derived from human anti-WNE antibodies and nucleic acid molecules encoding such immunoglobulins. The present invention also relates to methods of making human anti-WNE antibodies, compositions comprising these antibodies and methods of using the antibodies and compositions for diagnosis, prophylaxis and treatment.