Abstract: Objective To investigate the prognostic significance of BRAFV600E mutation in children with Langerhans cell histiocytosis (LCH), and to determine the prognostic factors of childhood LCH. Methods Children with newly diagnosed LCH were retrospectively included in this study who were enrolled in Beijing Children's Hospital affiliated to Capital Medical University between January 1, 2016 and December 31, 2017. BRAFV600E mutation in lesion tissues was detected by digital PCR method. Prognostic factors and the correlation of BRAFV600E mutation with clinical characteristics and prognosis were analyzed. Results A total of 140 patients with LCH were enrolled in this study, including 89 (63.6%) males and 51 females. The median age at diagnosis was 2.2 (0.1-15.7) years. For clinical classifications, there were 60 cases (42.9%) with single-system (SS) involvement, 47 cases (33.6%) with multi-system non-risk organ involvement (MS RO－), and 33 cases (23.6%) with risk organ involvement (MS RO+). The median follow-up time was 34.1 (0.9-50.7) months. During the follow-up, 70 patients (50.0%) developed progression or relapse; 12 patients (9.6%) had permanent sequelae; 3 patients (2.1%) died. The rate of 3-year progression free survival (PFS), event free survival (EFS) and overall survival (OS) was 48.9%±4.5%, 46.6%±4.4%, and 97.8%±1.2% respectively. BRAFV600E mutation was positive in 67.1% of 140 patients with LCH. There was a significant relationship between BRAFV600E mutation and clinical classifications. BRAFV600E was identified in 90.9% of patients with MS RO+ LCH, 53.2% of patients with MS RO－ LCH, and 65.0% of patients with SS LCH (P=0.001). Of patients with skin involvement, 77.8% was BRAFV600E positive, which was significantly higher than that of those without involvement (P=0.042). Of mutation positive patients, 57.4%had progression or relapse, which was significantly higher than that of negative patients (34.8%，P=0.019). However, there was no significant difference in the prognosis of patients with and without BRAFV600E mutation in the three clinical classifications. The multivariate analysis showed that only the RO+ was an independent prognostic factor of PFS in children with LCH (hazard ratio, HR=2.702, P=0.003), and pituitary involvement (HR=3.582，P<0.001), RO+ (HR=2.321, P=0.008) and ear involvement (HR=2.093, P=0.013) were independent prognostic factors of EFS. Conclusion BRAFV600E mutation was closely related to RO+ involvements in childhood LCH. The rate of progression/relapse of mutation-positive patients was significantly higher than that of mutation-negative patients, but BRAFV600E mutation was not an independent prognostic factor of childhood LCH.