Vasoplegia occurs in up to 16% of patients who undergo heart transplantation (HT) and is associated with significant morbidity and mortality. We present a case of a 61-year-old man with ischemic cardiomyopathy receiving sacubitril/valsartan (Entresto; Novartis, Cambridge, MA) who developed profound hypotension after HT. He was treated with intravenous methylene blue and high-dose vasopressors, but developed acute kidney injury requiring dialysis and a prolonged stay in the intensive care unit. This case supports a potent vasodilatory effect of sacubitril/valsartan, and if confirmed by other studies, might warrant consideration for withholding treatment while awaiting HT, particularly in patients with risk factors for vasoplegia.