The 1999 introduction of West Nile virus (WNV) into the United States has resulted in the largest epidemic of arboviral illness in the Western Hemisphere, with an estimated 2.5 million cases of mostly asymptomatic human infections since then. As a consequence, an increasing occurrence of WNV antibodies in plasma collected in the United States, and thus in intravenous immunoglobulin (IVIG) products, can be expected. Using an in vitro assay to investigate antibody function, rather then presence, almost 1000-fold differences in neutralization capacity were demonstrated between individual IVIG lots. In a mouse model of lethal WNV infection, treatment with IVIG of a higher WNV antibody titer protected recipients, whereas mice treated with control IVIG died. IVIG lots with higher WNV antibody titers would seem to be desirable for substitution therapy for people with immunodeficiencies.