Influenza is associated with a wide spectrum of respiratory and nonrespiratory complications, including neurologic manifestations, of variable disease severity. Influenza-associated encephalopathy (IAE) encompasses several clinical syndromes in which impaired consciousness and/or altered mental status and brain dysfunction may range from brief, mild, and self-limited to rapid progression to coma and death. The most severe clinical syndrome of IAE is acute necrotizing encephalopathy (ANE). Although thought to be rare, ANE has been associated with high mortality and high frequency of neurologic sequelae in survivors. Recently, consensus case definitions for ANE were proposed that include acute neurologic deterioration with neuroimaging findings of bilateral symmetric thalamic lesions and may also involve other areas of the brain such as the brainstem, cerebellum, and cerebral white matter. ANE can be triggered by multiple pathogens and has been described since the late 1970s in Japan, with some ANE cases identified during influenza epidemics. In the United States, pediatric deaths with IAE, and influenza-associated ANE (IANE) cases, have been reported, but no national surveillance exists for IAE or IANE.