Hypoglycemia (blood glucose less than 45 mg per deciliter [less than 2.5 mmol per liter]) occurred in seven of 19 healthy men who exercised to exhaustion on a cycle ergometer at 60 to 65 per cent of maximal aerobic power. The hypoglycemic subjects exercised for 15 to 70 minutes despite blood glucose levels of 25 to 48 mg per deciliter (1.4 to 2.7 mmol per liter), and their exhaustion time (mean +/- S.E.M., 142 +/- 15 minutes) was not significantly different from that of the euglycemic group (165 +/- 11). Plasma epinephrine was inversely related to blood glucose (P less than 0.01) and was three times higher in the hypoglycemic subjects (P less than 0.05). Glucose ingestion (40 or 80 g per hour) prevented the hypoglycemia and resulted in a smaller rise in plasma epinephrine but did not alter perceived exertion or consistently delay exhaustion. We conclude that hypoglycemia occurs in normal subjects during prolonged exercise and results in an exaggerated rise in plasma epinephrine. However, hypoglycemia fails to effect endurance, and its prevention does not consistently delay exhaustion.