A marked sexual dimorphism exists in healthy individuals in the pattern of blunted neuroendocrine and metabolic responses following antecedent stress. It is unknown whether significant gender related counterregulatory differences occur during prolonged, moderate exercise, following antecedent hypoglycemia in Type 1 diabetes (T1DM). Fourteen patients with T1DM (7 women and 7 men) were studied during 90min of euglycemic exercise at 50% VO2max, following two 2 hr episodes of previous-day euglycemia (5.0 mmol/L) or hypoglycemia of 2.9mmol/L. Men and women were matched for age, glycemic control, duration of diabetes, and exercise fitness, and had no history or evidence of autonomic neuropathy. Exercise was performed during constant "basal" i.v. infusion of regular insulin (1 U/hr) and a 20% dextrose infusion, as needed to maintain euglycemia. Plasma glucose and insulin levels were equivalent in men and women during all exercise and glucose clamp studies. Antecedent hypoglycemia produced a relatively greater (p<0.05) reduction of: glucagon, epinephrine, norepinephrine, growth hormone and metabolic (glucose kinetics) responses in men, as compared to women during next-day exercise. Following antecedent hypoglycemia, EGP was significantly reduced in men only, paralleling a reduction in the glucagon/insulin ratio and catecholamine responses. In conclusion, a marked sexual dimorphism exists in a wide spectrum of blunted counterregulatory responses to exercise in T1DM, following prior hypoglycemia. Key neuroendocrine (glucagon, catecholamines) and metabolic (EGP) homeostatic responses were better preserved during exercise in type 1 DM women following antecedent hypoglycemia. Preserved counterregulatory responses during exercise in type 1 DM women may confer greater protection against hypoglycemia as compared to males with type 1 DM.