Langerhans cell histiocytosis (LCH) is a rare disease affects any age and any organ; its presentations and outcome vary from self-healing lesions to life-threatening disseminated disease. This study evaluates the outcome of treating children diagnosed with Langerhans cell histiocytosis (LCH) at Oncology Center, Saudi Arabia. Procedure: Through a retrospective study design, the researchers reviewed the medical records and electronic files of all children (aged from 0-≤ 14 years) who had been diagnosed and treated for LCH at Princess Norah Oncology Center (PNOC), King Abdelaziz Medical City, Saudi Arabia, in the period from January 2000 to December 2019 (n=33). Results Males constituted (66.7%), with remarkable dominance of Saudis (93.9%). The median age at diagnosis was 28 months (IQR=49 months); (42.4%) were diagnosed before reaching their second birthday. Fourteen patients (42.4%) had multisystem (MS-LCH) involvement, of which 13 patients with risk organ (RO) (+) and one patient without risk organ (RO) (-). Most of the patients received LCH III protocols. Reactivation occurred in 11 patients (33.3%), and two deaths (6.1%) occurred in cases with MS (RO) (+) progressive disease. The overall survival was 93.9%; with no statistically significant difference in event free survival observed between patients with multisystem compared to single system involvement. Conclusion Excellent outcome of LCH is associated with single system involvement and worse outcome (reactivations, or morality) is determined by multi-organ involvement especially at younger age less than 24 months. Understanding of pathophysiology and genetic molecular background could lead a novel therapy that warrants a prospective clinical trial.