A 57-year-old man who had received treatment for B cell lymphoma presented with West Nile virus (WNV) meningoencephalitis. During his 99-day hospitalization, no WNV-specific antibodies were detected. In postmortem central nervous system samples obtained at autopsy, WNV RNA and WNV antigens were detected. This patient's case raises important issues related to the diagnosis, pathogenesis, and possible treatment of persistent WNV infection.