Spontaneous, prolonged hypoglycemia was observed in one nondiabetic and one mildly diabetic patient, both with chronic renal insufficiency. Although both patients had abnormal oral glucose tolerance tests, half-time disappearance of glucose was usually normal during intravenous glucose tolerance tests. Both patients developed persistent hypoglycemia during the tolbutamide tolerance test, but the insulin responses were not consistent with an islet cell adenoma. The hypoglycemia did not seem to reflect increased insulin secretion, increased insulin sensitivity or impaired glycogenolysis as assessed by the blood glucose response to glucagon. Although some factor associated with chronic renal disease was probably responsible for the hypoglycemia, the underlying mechanism was not defined.