Langerhans cell histiocytosis (LCH) is an inflammatory myeloid neoplasia with diverse clinical behaviour. In this article, we studied the clinical course, management and long-term outcomes of a paediatric cohort treated by our reference centre. We retrospectively studied 66 children with LCH, consecutively diagnosed by a Greek reference centre from 1974 to 2020. The patients had a median age of 3.9 (range 0.0-15.9) years, 39 and 6 patients were diagnosed with unifocal or multifocal single system disease and 14 and 7 had multisystem disease with or without risk organ involvement. No late occurrence of clinical neurodegenerative disease or diabetes insipidus were observed at a median follow-up period of 4.1 (range 0.5-27.7) years. The 10-year event-free survival and overall survival were 65.0% and 90.3% and improved significantly over a 45-year period. Survival was superior in single system than multisystem cases. BRAF V600E mutation was found in 8/14 tested patients. Reactivation occurred in 12/66 patients (18.2%); 11 achieved remission and one patient died after a second relapse. LCH survival rates significantly increased in our cohort over time. Reactivation occurred in 18.2% patients, but no late neurodegeneration was found. The prognostic value of single system disease status vs. multisystem LCH was confirmed. © 2020 Foundation Acta Paediatrica. Published by John Wiley & Sons Ltd.