Introduction: Persistent hypoglycemia in the setting of acute renal insufficiency while on sulfonylureas is potentially a life-threatening complication. A case of severe hypoglycemia in a diabetic with acute on chronic renal insufficiency while on glimepiride is described here. Case Report: A seventy-six years old man presented to our emergency department with gradually progressive generalized weakness, dyspnea on exertion and lightheadedness. His medical history included congestive heart failure, hypertension and chronic kidney disease from non-insulin dependent diabetes. He reported good compliance with his medications which included glimepiride, 2 mg daily. Patient’s spouse reported a blood sugar reading of 22 mg/dL at home which prompted the emergency department visit. On presentation, the patient was tachycardic, tachypneic and diaphoretic. Initial glucose meter reading was found to be 36 mg/dL and a blood glucose level on the metabolic panel was 49 mg/dL. Patient serum creatinine was 2.5 mg/dL, increased from a baseline of 1.8 mg/dL. While in the emergency room, the patient received 50% dextrose intravenously eventually requiring an intravenous infusion of 10% dextrose. Despite this treatment, the patient remained persistently hypoglycemic with blood sugars less than 80 mg/dL. A decision was made at this point to administer 50 micrograms of octreotide subcutaneously. Two hours later, the patient’s blood sugar started to improve and the intravenous 10% dextrose was discontinued. Eight hours later, the patient received another dose of 50 micrograms of octreotide and remained consistently euglycemic. Upon discharge, he was asked to discontinue glimepiride. Conclusion: Severe refractory hypoglycemia is a serious complication of sulfonylurea therapy in diabetics with renal insufficiency. Prompt recognition and initiation of octreotide are effective in reversing hypoglycemia in these instances rapidly and safely.