Purpose. An etiological treatment is currently lacking for Langerhans Cell Histiocytosis (LCH). Receptor activator of nuclear factor kappa B ligand (RANKL) appears to play a central role in the lesional immunological process inducing compensatory osteoprotegerin (OPG) activation. In a preliminary study we aimed to evaluate for the first time the use of denosumab, a RANKL inhibitor, as a targeted treatment strategy in LCH in order to support and enhance endogenous OPG action in order to control or alter the lesional immunological process. Procedures. Two adult female patients with painful osteolytic bone lesions and concomitant pulmonary involvement received bimonthly denosumab 120 mg in a total of 4 doses. Results. Both patients reported an immediate pain relief within the first two weeks following the 1st dose of denosumab. One month following the last dose an almost full remission of the initial osteolytic and lung lesions was observed, although an apparent new bone lesion was detected in one patient that was treated with a single intralesional steroid injection. No adverse events were recorded throughout the treatment period. Both patients have no active disease 6 months following the last denosumab dose. Conclusions. Denosumab could be considered an effective treatment option in adults with multisystem LCH also exerting a significant analgesic effect in bone lesions, warranting further investigation. (C) 2017 Elsevier Inc. All rights reserved.