Since encephalitis lethargica's (EL) prevalence in the 1920s, epidemiologic and clinical debate has persisted over whether EL was caused by, potentiated by, or merely coincident with the Spanish influenza pandemic. Epidemiologic analyses generally suggest that the disorders were coincidental. Beginning in the 1970s, modern experiments on archival brain samples mainly failed to confirm a direct relationship between influenza and EL. These experimental studies have technical limitations, e.g., the appropriateness of antibodies, polymerase chain reaction (PCR) primers and controls, and the extreme paucity and age of available material. These factors render the case against influenza less decisive than currently perceived. Nevertheless, there is little direct evidence supporting influenza in the etiology of EL. Almost 100 years after the EL epidemic, its etiology remains enigmatic, raising the possibility of a recurrence of EL in a future influenza pandemic.