Denosumab is a receptor activator of nuclear factor kappa-B (RANK) ligand inhibitor used in the treatment of osteoporosis. Blockade of RANK ligand prevents osteoclastic resorption of bone, but in doing so impairs the parathyroid hormone (PTH)-driven maintenance of serum calcium. A subsequent elevation of PTH remains active at sites other than bone, potentially lowering serum phosphate by inhibiting proximal tubular reabsorption. We present 2 patients who developed severe, symptomatic hypocalcemia after administration of denosumab. These patients provide an opportunity to describe the clinical course and treatment, including the need to consider a continuous calcium infusion, of severe, symptomatic hypocalcemia caused by denosumab.