Clofarabine (CLO) monotherapy reportedly induces a better clinical response in some patients with refractory Langerhans cell histiocytosis (LCH). We successfully treated two patients with refractory multisystem LCH with CLO monotherapy after recurrence. We administered 23 courses of CLO monotherapy in patient 1 and 4 courses in patient 2. Both patients achieved a durable complete response with acceptable adverse effects of transient myelosuppression. CLO monotherapy is a better therapeutic option for high efficacy and feasibility than other combination chemotherapies or allogeneic hematopoietic stem cell transplantation for refractory LCH.