West Nile virus (WNV) is a mosquito-borne virus that has caused a large number of deaths in the United States since the first outbreak in New York City in 1998. The outbreak initially was limited to the northeast but has since spread across the entire continental United States. WNV causes a variety of clinical symptoms, but the most severe consequences result from central nervous system infection, resulting in meningitis, encephalitis, or meningoencephalitis. We present a case of a 62-year-old male with metastatic cancer, who died as a result of WNV encephalitis. This is followed by a discussion on the epidemiology of WNV and a detailed summary of the methods and resources available to make a diagnosis of WNV infection postmortem. The material presented in the discussion should provide the forensic pathologist with all the information necessary to make a diagnosis of WNV infection postmortem. If nothing else, the routine collection and storage of serum, cerebrospinal fluid, and tissue for every case can enable the forensic pathologist to make this diagnosis even in cases in which WNV is not suspected until after autopsy.