Abstract Disclosure: M. Thomas: None. N. Janakiram: None. J. Leary: None. K.E. Foster-Schubert: None. R.R. Narla: None. Background: Electrolyte disorders are commonly seen with chemotherapy (CTX) agents. Cetuximab is an epidermal growth factor receptor inhibitor and irinotecan is topoisomerase 1 inhibitor. Both agents have been associated with hypomagnesemia which can adversely lead to hypocalcemia (HC). Case: A 66-year-old woman with osteoporosis (last bisphosphonate use was 24 months ago), primary hyperparathyroidism status post parathyroidectomy in 2015 (R inferior and superior glands) and 2017 (L inferior gland) with recent diagnosis of metastatic adenocarcinoma of unknown primary who presented with nausea, tetany, leg cramps and found to have severe HC of corrected calcium (CCa) of 5.7, a week post-chemotherapy. On the day of her CTX, her CCa was 7.0, ionized calcium (iCal) of 1.7 with Magnesium (Mg) of 2.0; she received IV calcium (Ca), then underwent CTX. She was prescribed Ca supplements and reports adherence. She returned endorsing the above symptoms with positive Chvostek and Trousseau sign on exam. Labs were notable for CCa of 5.7, iCal of 1.6, Mg of 1.6, Phosphorus of 4.5, PTH 123 (ULN 65), 25-OH vitamin D of 28.6 and normal eGFR. She was hospitalized and received multiple infusions of IV Ca and CCa improved to 7.5. She was discharged on Ca carbonate 1000 mg TID, Mg oxide 420 mg BID and Vitamin D. Before her second cycle of CTX with same agents, she received IV Ca for CCa of 7.3. She remained on Ca and Mg supplements. One week later, she endorsed paresthesia, diarrhea and was admitted again for HC. She was initiated on calcitriol on this admission and 24-hour urine studies showed low Ca excretion and elevated fractional excretion of magnesium (FeMg). Her CCa was 8.0 and she was discharged on calcitriol 0.25 mg BID. Oncology discontinued this CTX regimen. Her HC resolved and calcitriol and Ca supplements were gradually weaned off. Discussion: After both rounds of cetuximab and irinotecan, our patient developed profound HC without hypomagnesemia. Cetuximab can cause occasional Mg wasting syndrome with inappropriate urinary excretion. However, she was started on Mg since her first hospitalization despite normal serum Mg levels. Interestingly, her 24-hour urine studies revealed FeMg of 6.5% suggestive of renal Mg wasting. In the literature, there is a case report of severe HC with irinotecan but they had speculated germline mutations in Ca metabolism genes. It remains unclear how these CTX agents impact Ca homeostasis. It is difficult to discern if the severe HC in our patient could be attributed to Mg wasting with normal Mg levels. It is evident that her HC was associated with the timing of her CTX regimen. Therapy for HC can be complex, involves short- and long-term interventions, and correction is critical. Serum Ca surveillance before and during CTX management of cancer patients may reveal more instances and provide insight into the exact mechanisms. Presentation: Saturday, June 17, 2023