: The etiology and pathophysiology of Langerhans cell histiocytosis (LCH) remain elusive. The 3-year survival in pediatric multisystem LCH is still around 80%, and children with risk organ involvement (i.e., liver, spleen, hematopoietic system, or lungs) have a less favorable outcome. To further elucidate the pathogenesis of LCH in the search for a rationale cure, the authors investigated intracellular synthesis of tumor necrosis factor (TNF), interleukin (IL)-11, and leukemia inhibitory factor (LIF) from biopsied lesions. : Lesional cells were obtained by fine-needle aspiration biopsy from nine children with LCH. The study was accomplished by the use of an immunofluorescence staining method that allowed cytokine-producing cells to be differentiated from cytokine-binding cells. : All patients had histiocytes expressing TNF. Seven patients had histiocytes expressing IL-11 and six patients had histiocytes expressing LIF. The two children with the highest proportion of histiocytes displaying TNF and the three with the highest proportion of histiocytes expressing IL-11 and LIF all had risk organ involvement. Two-color staining revealed that histiocytes expressing TNF, IL-11, and LIF co-expressed CD1a molecules. : These observations suggest that LCH represents a cytokine-driven condition partially mediated by TNF, IL-11, and LIF. These three cytokines are all osteoclastogenic, suggesting a pathogenetic pathway for the osteolytic lesions in LCH. Furthermore, thrombocytosis in LCH may be explained by IL-11 and LIF activity.