We compared counterregulatory metabolic and hormonal responses in 8 normal controls with responses in 16 Type I (insulin-dependent) diabetics, 7 of whom had had repeated attacks of severe hypoglycemia, in an effort to determine whether these responses are related to the occurrence of hypoglycemia in the latter group. In response to insulin-induced hypoglycemia, peak values for glucose production (5.7 +/- 0.5 vs. 2.5 +/- 0.3 mg per kilogram of body weight per minute) (P less than 0.0001), glucagon (195 +/- 26 vs. 93 +/- 18 pg per milliliter) (P less than 0.0001), and growth hormone (63 +/- 8 vs. 37 +/- 5 ng per milliliter) (P less than 0.006) were significantly higher in the controls than in the diabetics. However, peak values for glucose production, glucagon, epinephrine, norepinephrine, cortisol, and growth hormone were similar in the diabetics with and without clinical hypoglycemia. Thus, with the present dose and method of insulin administration we were unable to predict the presence of severe hypoglycemic reactions in a group of Type I diabetics. Although deficient counterregulatory hormone responses are important in the pathogenesis of hypoglycemic reactions, we conclude that other factors in the daily lives of such patients also play a major part in determining whether reactions will occur.