Although the prognosis of acute disseminated encephalitis (ADEM) has generally been reported as favorable, in a small subset of patients, fulminant cerebral edema requiring critical care and surgical management may develop. This article presents a 56-year-old woman who developed ADEM and died of central brain herniation secondary to medically intractable cerebral edema. Following this experience, we encountered a 32-year-old man who also developed central brain herniation despite best medical management. We performed an urgent decompressive hemicraniectomy and frontal lobectomy followed by intensive intracranial pressure management. Few recommendations are available to guide neurologists and neurosurgeons in the management of medically intractable cerebral edema of ADEM. In this report, we present our experience with two severe cases of ADEM, review the pertinent literature, and discuss options for improved management of fulminant cases.