West Nile virus was identified by immunohistochemistry (IHC) and polymerase chain reaction (PCR) as the etiologic agent in four encephalitis fatalities in New York City in the late summer of 1999. Fever and profound muscle weakness were the predominant symptoms. Autopsy disclosed encephalitis in two instances and meningoencephalitis in the remaining two. The inflammation was mostly mononuclear and formed microglial nodules and perivascular clusters in the white and gray matter. The brain stem, particularly the medulla, was involved most extensively. In two brains, cranial nerve roots had endoneural mononuclear inflammtion. In addition, one person had acute pancreatitis. On the basis of our experience, we offer recommendations for the autopsy evaluation of suspected WNV fatalities.