Objective To explore the clinical features of Langerhans cell histiocytosis (LCH) with sclerosing cholangitis (SC) as the first manifestation, aiming to enhance the understanding of LCH in children with liver involvement. Methods Cases in the electronic medical record system of Guangzhou Women and Children’s Medical Center who were diagnosed with SC at the first visit and subsequently diagnosed with LCH were retrospectively analyzed. The clinical manifestations, lab examination, imaging, treatment process, and prognosis were summarized. Results There were six cases of LCH with SC as the first manifestation. The female-to-male ratio was 5:1, and the median age was 12 months (ranging from 12 to 22 months). All six patients present cholestasis as the first manifestation, which was characterized by abnormalities in liver function, mainly elevated γ-glutamyl transpeptidase and direct bilirubin levels. Their magnetic resonance cholangiopancreatography (MRCP) showed focal intrahepatic bile duct stenosis and dilatation, leading to the radiological diagnosis of SC. Five cases were diagnosed with LCH after immunohistochemical staining of the skin rash tissue, four of which presented with SC accompanied by skin rash; one case had SC alone, and the diagnosis was confirmed by a tissue biopsy of skin rash that developed over following two months. One presented with SC accompanied by diabetes insipidus caused by pituitary involvement, whose 2 Liver puncture biopsies only showed nodular cirrhosis, and LCH was confirmed by immunohistochemical staining of liver mass tissue after liver transplantation. Six cases received first-line chemotherapy protocol after LCH diagnosis. One showed systemic remission after liver transplantation with chemotherapy and symptomatic treatment. Four showed improvement in systemic condition but no significant improvement in the liver imaging examinations at the end of the follow-up. One died of liver failure. Conclusions SC is one of the advanced and severe form of LCH liver involvement, with or without other tissue and organ lesions. Diagnosis requires a combination of characteristic skin rash, osteolytic changes, and tissue involvement such as pituitary gland, as well as a pathological diagnosis.The prognosis of SC due to LCH is poor. SC in combination with cirrhosis, especially with portal hypertension, intractable itching of the skin, or growth retardation, may be considered for liver transplantation, and chemotherapy may be a therapeutic approach with a better prognosis after the operation.