High-risk multisystem organ (RO+) Langerhans cell histiocytosis (LCH) has the least survival. We present the outcome of RO+ LCH in a pediatric single center. Fifty RO+ LCH patients, treated between 07/2007 and 07/2015, were retrospectively analyzed. Induction vinblastine (VBL) and prednisone (PRED) with intermediate-dose methotrexate (idMTX) was adopted until 2012 (n=20) wherein idMTX was omitted (n=30). The 3-year overall survival (OS) of MTX and non-MTX groups was 75% and 63%, respectively, P=0.537, while the event-free survival (EFS) was 36.9% and 13.2%, respectively, P=0.005. At week 12 of induction, "better status" was obtained in 80% of those receiving MTX, and 55% of those who were not. The statistically significant factors associated with both poor OS and EFS were trihemopoietic cytopenias, hepatic dysfunction, tri RO+ combination, and single induction. The factors associated with disease progression (DP) on induction were trihemopoietic cytopenias, hepatic dysfunction, and lack of idMTX, while those for disease reactivations (REA), the season of autumn/winter, lung disease, male sex, and idMTX were the associated factors. The 1-year OS was remarkably affected with the occurrence of DP versus REA versus none, wherein it was 47%, 93%, and 95%, respectively, P=0.001. In conclusion, idMTX is associated with better EFS. DP on induction remains of dismal prognosis in relation to disease REA afterwards. Risk stratification should highlight the role of trihemopoietic cytopenias, hepatic dysfunction, tri RO+, central nervous system risk site, and lung association.