Erdheim–Chester disease (ECD) is a rare non-Langerhans cell histiocytosis characterized by tissue infiltration of lipid-laden macrophages, multinucleated giant cells, and inflammatory infiltrate of lymphocytes and histiocytes. The disease typically involves long bone, but may also affect the central nervous system, the orbit, retroperitoneal organs, and the lungs. Patients with visceral involvement tend to have poorer outcome. There is no proven effective treatment for ECD to date. However, recent data suggested the potential use of bisphosphonates for the treatment of this rare disease. Here we report a case of biopsy-proven skeletal ECD, who received treatment with zoledronic acid, an aminobisphosphonate, with remarkable clinical improvement. We also discuss possible mechanisms of action of bisphosphonates in this disorder, especially their roles in inhibition of inflammatory cytokines and macrophage infiltration.