Reported neurologic manifestations of novel H1N1 influenza have included seizure, meningoencephalitis, and acute necrotizing encephalopathy. We describe the first series of pediatric patients presenting during the second wave of the US novel H1N1 pandemic, with protracted seizures, severe encephalopathy/encephalitis, and acute disseminated encephalomyelitis. In addition to prominent radiographic abnormalities, we provide the first observation and description of associated cerebrospinal fluid abnormalities.