The aim of this study was to determine whether sex-related differences occur in counterregulatory responses to hypoglycemia in adult type 1 diabetic patients. Experiments were carried out on 16 (8 men/8 women) type 1 diabetic patients and compared with 16 (8 men/8 women) age- and weight-matched normal individuals. Men and women with type 1 diabetes were matched for age (26+/-2 vs. 25+/-1 years), duration of diabetes (9+/-1 vs. 8+/-1 years), glycemic control (HbA1c 7.7+/-0.3 vs. 7.8+/-0.2%), and weight (BMI 22.8+/-1 vs. 22.1+/-1 kg/m2), respectively. After normalizing plasma glucose overnight, patients underwent a 2-h hyperinsulinemic-hypoglycemic clamp study. Plasma glucose (3.0+/-0.1 mmol/l) and insulin (510+/-48 pmol/l) levels were equated in all groups. Plasma epinephrine, norepinephrine, growth hormone (GH), muscle sympathetic nerve activity (MSNA), and endogenous glucose production (EGP) responses were significantly lower (P<0.01) in type 1 diabetic women compared with men. Autonomic symptom scores, lipid oxidation, nonesterified fatty acids (NEFAs), and glycerol responses were equivalent between men and women with type 1 diabetes despite significantly reduced sympathoadrenal and MSNA responses in women. Autonomic nervous system (ANS) and EGP responses were equivalent in type 1 diabetic and normal individuals. However, lipid oxidation (assessed by indirect calorimetry), glycerol, and NEFA responses were increased (P<0.01) in type 1 diabetic patients compared with normal control subjects. We conclude that counterregulatory responses to fixed hypoglycemia differ markedly in men and women with type 1 diabetes: 1) sympathetic nervous system, GH, and EGP responses are significantly reduced in type 1 diabetic women, 2) autonomic symptom awareness and lipolytic responses appear to be relatively increased in type 1 diabetic women compared with men, and 3) during conditions of similar hyperinsulinemic hypoglycemia and ANS drive, lipid oxidation and lipolytic responses can be increased in type 1 diabetic patients compared with normal individuals.