Infection with West Nile virus (WNV) ranges from causing no symptoms to causing non-specific fever, meningitis, meningo-encephalitis and death. Advanced age and immunosuppression are the greatest risk factors for the development of encephalitis or other neurologic manifestations of WNV. We report the first fatal case of primary WNV infection in an orthotopic heart transplant recipient. We reviewed the literature on WNV infection in the general population and in immunocompromised hosts. As WNV becomes more common in the United States, it will become an increasing threat to our transplant population.