Background: Langerhans cell histiocytosis (LCH) is a rare myeloid neoplasm with inflammatory characteristics. This study aims to investigate the correlation between sCD25 levels and clinical characteristics and prognosis in pediatric LCH. Procedure: Serum sCD25 levels were measured in 370 LCH patients under 18 years old using ELISA assays. The patients were divided into two cohorts based on different treatment regiments. We further assessed the predictive value for prognosis impact of sCD25 in a test cohort, which was validated in the independent validation cohort. Results: The median serum sCD25 level at diagnosis was 3908 pg/ml (range: 231-44 000). sCD25 level was significantly higher in MS RO+ LCH patients compared to SS LCH patients ( P<0.001). Patients with increased sCD25 were more likely have involvement of risk organs, skin, lung, lymph node, or pituitary (all P < 0.05). sCD25 level could predict LCH progression and relapse with an area under the ROC curve of 60.6%. The best cutoff value was determined at 2921 pg/ml. High-sCD25 group had a significantly worse progression-free survival than those in the low-sCD25 group ( P < 0.05). Conclusion: Elevated serum sCD25 levels at initial diagnosis was associated with high-risk clinical features and worse prognosis. sCD25 levels can predict the progression/recurrence of LCH after treatment with first-line chemotherapy.