Multiple sclerosis (MS) is the most frequent demyelinating disorder of the central nervous system (CNS). However, at presentation, it is frequently difficult to differentiate between malignant MS (MMS) and other fulminant CNS demyelinating diseases like acute disseminated encephalomyelitis (ADEM). The literature contains many case reports of ADEM but few series. We report on four representative cases of acute demyelinating diseases, together with evaluation of treatment, course and follow-up. We also present clinical, laboratory, neuropathologic, neuroimaging and data on therapeutic options, including follow-up, in order to establish distinguishing characteristics of MMS and ADEM. Good clinical outcome from a postinfectious, monophasic episode, correlating with regressive demyelinating lesions on MRI, after more than 2 years differentiate best. Therapeutic efficacy, prior infection and initial MRI lesions seem to be of limited value. Despite the advances of neuroimaging and laboratory techniques, objective parameters are still missing, but findings on basic immunologic mechanisms of humoral and cellular response might provide further insight. Copyright 1999 Harcourt Publishers Ltd.