Neonatal enteroviral hepatitis carries high morbidity and mortality. We treated three full term neonates with severe enteroviral hepatitis with pleconaril on an open label compassionate use protocol. Each mother had history of a viral-like syndrome within 1 week before delivery. The neonates presented at 4 to 5 days of age with fulminant hepatic failure with severe coagulopathy, and each yielded an echovirus. All were treated with pleconaril (VP63843) at 5 mg/kg every 8 h by nasogastric tube. Two of the three neonates with life-threatening enteroviral hepatitis recovered fully. Further experience with pleconaril for neonatal enteroviral hepatitis is warranted.