Abstract Background: Currently, there is no widely accepted clinical practice guideline for the management of severe hypercalcemia in hospitalized patients. Objective: The purpose of this project was to analyze management of hypercalcemia in hospitalized patients at an academic medical center, then establish and implement a clinical practice guideline for hypercalcemia treatment. Design: Retrospective chart review of all patients admitted for management of hypercalcemia over 37 consecutive months. Setting: Urban academic tertiary referral center Measurements: We examined which calcium- lowering medications were used, how often 2 medications were needed, average time to normocalcemia, incidence of hypocalcemia post treatment, serum phosphorus nadir and serum creatinine peak. We also assessed medication appropriateness (dose and frequency). Results: Seventy-two patients were included; 58 patients with hypercalcemia of malignancy and 14 patients with hypercalcemia of other diagnoses. In the malignancy group the most common treatment was a combination of calcitonin + bisphosphonate (43%), followed by bisphosphonate alone (29%) and calcitonin alone (24%). In the non-malignancy group, calcitonin alone was used in 50%, calcitonin + bisphosphonate in 21% and a bisphosphonate alone in 14%. Denosumab was rarely used in both groups. The median time to normocalcemia was 3.0 days irrespective of diagnostic group. Seventy two percent of the patients with malignancy and 86% of the non-malignancy group achieved normocalcemia. The incidence of hypocalcemia was 21% (12/58) in the malignancy subgroup and 29% (4/14) in the others after treatment. Serum creatinine did not change from baseline to post-treatment in either population. Median serum phosphorus dropped from 2.9 mg/dL to 1.8 mg/dL in the malignancy group and 4.2 mg/dL to 2.1 mg/dL in the non-malignancy group. Only 41% of patients that received calcitonin, were given recommended dose, route, and frequency. Conclusion: Based on the results of this study, a hypercalcemia treatment guideline was developed, highlighting appropriate medication dose and frequency. This guideline recommends zoledronic acid alone for asymptomatic malignancy patients, and in combination with calcitonin for symptomatic patients. In contrast, calcitonin alone is considered first line for non-malignant conditions.