Abstract Disclosure: S. Elahi: None. S. Baim: None. Introduction: Acute myeloid leukemia (AML) and other leukemias do not commonly induce hypercalcemia of malignancy (HCM). Limited previous reports of AML-related HCM have largely attributed cases to inflammatory-cytokine-mediated osteoclast activation, with rare reports of calcitriol-mediated HCM and ectopic parathyroid hormone (PTH) production. We describe an unusual case of AML-induced HCM caused by direct leukemic bone invasion, which responded to bisphosphonate therapy. Case Presentation: A 59-year-old female presented with spontaneous bruising and severe leukocytosis concerning for AML. The diagnosis was confirmed by flow cytometry and bone marrow biopsy. Imaging did not reveal any gross destructive bone lesions, but showed soft tissue nodules in the lumbar region which biopsy revealed to be myeloid sarcoma. Prior to initiation of chemotherapy, the patient developed severe hypercalcemia that was treated with aggressive intravenous hydration and zoledronic acid. Intrathecal chemotherapy and high-dose glucocorticoid therapy were initiated thereafter with normalization of serum calcium levels. PTH levels were suppressed. Calcitriol and PTHrP were below normal and undetectable, respectively. Bone turnover markers (C-telopeptide and bone-specific alkaline phosphatase) were significantly elevated prior to administration of zoledronic acid and normalized post-therapy. Calcium levels did not rebound after several interruptions in chemotherapy. Bone marrow biopsy showed focal areas of erosion in trabecular bone consistent with diffuse microscopic osteolytic disease. The patient developed bisphosphonate-induced hypocalcemia following treatment with zoledronic acid, which normalized with treatment with oral calcium carbonate. Discussion: Hypercalcemia of malignancy is a very unusual consequence of AML. No currently-published reports of this phenomenon have described biopsy-proven diffuse microscopic bone erosion associated with AML. We attribute our patient’s severe HCM to large-scale focal bone erosion by AML, independent of and/or associated with concurrent bone resorption mediated by inflammatory cytokines. A single dose of zoledronic acid, a potent suppressor of bone remodeling, achieved long term control of calcium for our patient despite interruption of chemotherapy. Bisphosphonate therapy should be considered an early treatment of HCM in patients with AML due to several potential mechanisms that result in direct calcium release from the skeleton. Presentation: Saturday, June 17, 2023