The discovery of the MAPK pathway mutations in lesions of patients with Langerhans cell histiocytosis (LCH) has made targeted therapy an important therapeutic approach for these patients. Theoretically, the RAF-independent mutation MAP2K1^E102_I103del is naturally resistant to allosteric MEK inhibitors. We report a dramatic response to MEK inhibitor trametinib in a case of LCH with MAP2K1^E102_I103del mutation, which indicates that trametinib is worth trying in recurrence and refractory LCH patients with MAP2K1^E102_I103del . Trial Registration: The authors have confirmed clinical trial registration is not needed for this submission.