Introduction. Acute disseminated encephalomyelitis (ADEM), a demyelinating inflammatory disease, probably with an autoimmune component, has an acute or subacute onset and presents with multifocal lesions of the central nervous system (CNS). In many cases, it is necessary to carry out the differential diagnosis with Multiple Sclerosis (MS), a chronic and progressive inflammatory disease of the CNS, which appears in young adults between 20 and 40 years old, but can also affect children, after a suspected ADEM. The purpose of the study is the evolutionary estimation of the specific clinical characteristics of the first demyelinating episode of ADEM, to determine the differential diagnosis with MS. Material and methods. A retrospective study was carried out during the years 2010 - 2022, by analyzing the medical records of 42 children and adolescents (19 girls and 23 boys), who suffered from an acute demyelinating disease of the CNS and presented at the first episode of the disease with an abnormal magnetic resonance image of the brain (MRI). The mean age of children with ADEM (6 years and 8 months) and those with MS (14 years and 7 months) was calculated. According to the definition proposed by the Pediatric MS Study Group, regarding the nosologies studied, the diagnosis of ADEM was confirmed after 3 months from the onset of the first episode. For diagnostic accuracy, MS patients were assigned a final diagnosis after long-term follow-up. The average age of those with ADEM was 6 years and 8 months, and of those with MS – 14 years and 7 months. In the study, we used the definitions proposed by the Pediatric MS Study Group, regarding the nosologies studied. The diagnosis of ADEM was confirmed 3 months after the onset of the first episode. MS patients were assigned a final diagnosis after long-term follow-up. Results. Among the 42 children who were initially confirmed with ADEM 3 months after the first episode, only 3 (7%) of them presented with the multifocal form of the disease. In evolution, 18 (43%) children were diagnosed with ADEM, and 24 (57%) – with MS. The duration of follow-up was 6 years and 8 months in patients with monophasic ADEM form and 5 years and 6 months in patients with relapses of the disease. The encephalopathy was present in 13 (72%) of the ADEM patients while none of the MS patients had encephalopathy. At the initial stage of the disease, the immunological manifestations – oligoclonal bands in the cerebrospinal fluid (41.7%) and the increased immunoglobulin G index (75%), as well as the imaging ones – periventricular perpendicular ovoid lesions (58%), correlated with the outcome of MS. Only a few clinical features differed between ADEM and MS at first presentation. Encephalopathy, when present, definitely rules out the diagnosis of MS. Conclusions. The distinct features of MS and ADEM can be recognized at the initial presentation of the disease in most patients. Certainly, children presenting with a first demyelinating event should be cautiously evaluated for known MS risk factors. It should always be considered that the first cerebral demyelinating event may be a first attack of MS, therefore these children should be monitored for future relapses and early treatment considered in patients at high risk of MS.