This report describes a 53-year-old female individual with known arginine vasopressin deficiency (AVP-D) due to a recurrent Rathke cleft cyst (RCC), with asymptomatic severe hyponatremia (sodium 121 mEq/L [SI: 121 mmol/L]; reference range 135-145 mEq/L [SI: 135-145 mmol/L]) in the setting of several months of tirzepatide use for weight loss. On review of the literature this is the third case of severe hyponatremia (sodium ≤125 mEq/L [SI: ≤125 mmol/L]) reported with the use of tirzepatide and first case in someone with AVP-D. Although hyponatremia associated with tirzepatide is rare, it poses a significant risk for individuals with AVP-D, who are already predisposed to hyponatremia. Clinicians should remain vigilant regarding this potential complication, provide education on desmopressin escape strategies, and carefully consider reductions in desmopressin dosing when co-administering with tirzepatide.