Abstract Disclosure: M.S. Martinez Cruz: None. T.G. Lozovoy Madsen-Barbosa: None. C.J. Haas: None. Introduction: In rare cases, foreign body granuloma (FBG) reaction is so vast that it leads to severe systemic disease, including increased granuloma-mediated production of calcitriol. Case Description: A 42-year-old woman was referred to the ED due to elevated serum calcium and worsening GFR on routine blood work. She endorsed a two-week of generalized weakness, myalgias, polyuria, polydipsia, and intermittent constipation with prior episodes of such symptomatology. On her first presentation, severe hypercalcemia (13.8 mg/dL), acute-on-chronic renal disease, a normal TSH, an appropriately low PTH, elevated PTHrP, a low 25-hydroxy vitamin D, and a normal 1,25 dihydroxy-vitamin D were noted. She was treated with IV fluids and zoledronic acid 4mg IV one time with subsequent normalization of calcium levels. Six months later, she was re-admitted with similar complaints. Additional blood workup was unremarkable, including urine and serum protein electrophoresis and kappa/lambda ratio. She once again presented with similar complaints; additional workup revealed a normal 25-hydroxy vitamin D, mildly elevated serum angiotensin-converting enzyme, and a negative QuantiFERON-TB gold, but a marked elevation of 1,25 dihydroxy-vitamin D (138 pg/mL). She admitted to subcutaneous silicone filler injections in the lips, cheeks, and hips applied by a non-healthcare provider six years ago. She described that one year after the injections, she had noted intermittently indurated erythematous areas in the skin of the hips and upper lateral thighs that were notably tender to palpation. Diagnostic imaging included a whole-body PET-CT that demonstrated moderate FDG uptake within the subcutaneous adipose tissue of the lateral aspect of bilateral gluteal regions extending from the iliac crests to the upper thighs. She was diagnosed with silicone filler injection-induced hypercalcemia secondary to granulomatous inflammation and initiated on prednisone 20 mg PO daily with progressive normalization in her hypercalcemia (9.7 mg/dl) a month after initiation of treatment. Unique features/Teaching points: FBG reactions occur more commonly against permanent fillers like silicone, especially if injected in larger volumes and highly vasculature areas like hips or buttocks. These reactions may occur years after the initial injection. In rare cases, significant granulomatous immune response leads to the overactivity of 1-alpha-hydroxylase in activated macrophages, resulting in uncontrolled overproduction of calcitriol and, subsequently, hypercalcemia. FBG reactions may also cause increased levels of PTHrP, further contributing to hypercalcemia. Treatment focuses on general hypercalcemia management and FBG remission, most effectively achieved with anti-inflammatory corticosteroid doses. Further studies are needed to evaluate long-term treatment efficacy. Presentation: Friday, June 16, 2023