Encephalitis lethargica (EL) was a complex and mysterious disease that appeared around the same time as the great influenza pandemic of 1918. The contemporaneous relationship of the 2 diseases led to speculation that they were causally related. Contemporary and subsequent observers conjectured that the influenza virus, directly responsible for the deaths of more than 20 million people, might also have been the cause of EL. A review of the extensive literature by observers of the EL epidemic suggests that most contemporary clinicians, epidemiologists, and pathologists rejected the theory that the 1918 influenza virus was directly responsible for EL. Disappearance of the acute form of EL during the 1920s has precluded direct study of this entity. However, modern molecular biology techniques have made it possible to examine archival tissue samples from victims of the 1918 pandemic in order to detect and study the genetic structure of the killer virus. Similarly, tissue samples from EL victims can now be examined for evidence of infection by the 1918 influenza virus.