We describe 2 patients with West Nile virus (WNV) encephalitis who were treated experimentally with interferon (IFN)-alpha. Both patients demonstrated substantial improvement in mentation and speech on the second day of experimental therapy, and neither required endotracheal intubation or admission to the intensive care unit during hospitalization. Moreover, during the 9-month follow-up period, one patient achieved complete recovery, and the other nearly achieved complete resolution of sequelae. To our knowledge, this is the first published report of the use of IFN-alpha to treat WNV encephalitis. Clinical trials are underway to further define the role of this therapy in persons with WNV encephalitis.