WNV infection can cause meningoencephalitis (MNE) and acute flaccid paralysis (AFP). Both syndromes are associated with high morbidity and mortality. Interferon alpha-2b (IFN-alpha-2b) inhibits WNV replication in vitro. To date, 5 patients with WNV-CNS disease have recovered neurologic function with IFN-alpha-2b. We report the first failure of IFN-alpha-2b in the treatment of WNV-MNE-AFP.