Multiple sclerosis (MS) manifesting before age 18 years is defined as pediatric MS (pMS). We analysed plasma proteins in pMS by an untargeted proteomic approach. Patients with pMS (Group pMS, n = 33), patients with demyelinating disease not meeting pMS diagnostic criteria (unclassified demyelinating disease, Group U, n = 4) and age-matched healthy subjects (Group C, n = 40) were included. Plasma proteomic analysis was performed using Q-TOF LC/MS. Proteins having fold change >1.2 and found to be statistically different ( p < 0.05) between the groups were identified and discussed with a clinical perspective. Group pMS had higher alpha 1B glycoprotein (A1BG), complement factor B (CFB), plasminogen (PLG), alpha-2-antiplasmin (alpha(2)-AP, SERPINF2), inter alpha trypsin inhibitor heavy chain H2 (ITIH2), and lower centrosomal protein of 290 (CEP290) and F-box/LRR-repeat protein 17 (FBXL17) concentrations than Group C. Measurements from Group U, whose definite diagnoses were established as pMS ( n = 3) and myelin oligodendrocyte glycoprotein antibody-associated disease ( n = 1) on follow-up after the study, were statistically close to the results of Group pMS. Plasma protein changes observed in our study were related to the inflammation, coagulation and oxidative stress pathways. If confirmed and validated in larger groups, these results may indicate potential biomarker(s) for demyelinating diseases at proteome level and could encourage studies for the development of novel diagnostic kits.