West Nile Virus (WNV) is a mosquito-borne flavivirus, which has been known to cause human infection in Africa, the Middle East, and southwestern Asia. It has also been isolated in Australia and sporadically in Europe but never in the Americas. Clinical features include acute fever, severe myalgias, headache, conjunctivitis, lymphadenopathy, and a roseolar rash. Rarely is encephalitis or meningitis seen. During the month of August 1999, a cluster of 5 patients with fever, confusion, and weakness were admitted to the intensive care unit of the same hospital in New York City. Ultimately 4 of the 5 developed flaccid paralysis and required ventilatory support. Three patients with less-severe cases presented shortly thereafter. With the assistance of the New York City and New York State health departments and the Centers for Disease Control and Prevention, these were documented as the first cases of WNV infection on this continent.