Diabetic ketoacidosis has been described as a rare complication of acromegaly and may be observed in 1% of affected patients. The well-described direct lipolytic effect of growth hormone results in increased availability of free fatty acids (FFAs) for hepatic ketogenesis and is an important pathogenic event. More recently, ketoacidosis has been identified as an important complication of sodium-glucose-transport-protein 2 inhibitors (SGLT2i). Increased pancreatic glucagon secretion, impaired renal ketone body clearance, and an increase in FFA concentrations secondary to decreased insulin concentrations are likely precipitating factors. We report a case of rapid-onset severe ketoacidosis within 2 days after adding empagliflozin to metformin, sitagliptin, and gliclazide in a presumably type 2 diabetic patient with unrecognized acromegaly and chronic hyperglycemia. Transsphenoidal resection of the growth-hormone secreting macroadenoma restored normal growth-hormone and insulinlike growth factor 1 concentrations and the diabetes was well controlled thereafter. We hypothesize that SGLT2i, through their intrinsic effects on ketone body metabolism, may possibly precipitate ketoacidosis in patients with active acromegaly and diabetes mellitus.