AbstractJuvenile xanthogranuloma (JXG) is generally a benign, self‐limited histiocytic disorder of the skin. We report two cases of multisystem JXG presenting with clinical features more commonly seen in Langerhans cell histiocytosis (LCH), including diabetes insipidus and lytic bony lesions. Histologically, the skin lesions demonstrated a histiocytic dermal infiltrate that stained for CD‐68, but S‐100 and CD1a stains were negative. Treatment according to LCH‐based chemotherapy regimens resulted in prompt resolution of symptoms. A literature review of multisystem JXG cases treated with chemotherapy suggests that symptomatic patients can successfully be treated with LCH‐based regimens that include both corticosteroids and vinca alkaloids. Pediatr Blood Cancer 2008;51:130–133. © 2008 Wiley‐Liss, Inc.