This study of patients with insulin-dependent diabetes mellitus (IDDM) and hypoglycemia unawareness examines the effect of a period of less strict glycemic control on the defective counter-regulatory hormonal responses to and impaired awareness of hypoglycemia. In seven patients with IDDM with strict glycemic control and hypoglycemia unawareness, responses were studied with the use of a hyperinsulinemic hypoglycemic clamp test before and after 3 months of test treatment, which aimed at increasing daily mean blood glucose levels to 8 to 10 mmol/L, based on self-monitoring four times per day. The 3 months of test treatment elevated the patients' levels of glycosylated hemoglobin HbAlc from a mean of 6.9% (standard error [SE] 0.3%) at baseline to 8.0% (SE 0.3%, p < 0.05) and decreased the number of episodes of hypoglycemia (blood glucose level less than 3.0 mmol/L) per patient from a mean of 4.7 (SE 1.3) per week to 1.9 (SE 0.5) per week (p < 0.05). Although the same nadir (2.2 mmol/L) and duration of hypoglycemia were reached during each of the two clamp tests, the scores for sweating and lack of concentration were improved (p < 0.05) at the second test. The release of growth hormone and epinephrine during hypoglycemia were significantly improved (p < 0.05) at the second test, whereas the glucagon, cortisol and norepinephrine responses were unchanged. There were no significant differences in the results of the autonomic and cognitive function tests between the two tests. The results suggest that impaired hormonal and symptomatic responses to hypoglycemia in IDDM can be partially reversed by a modest rise in glucose levels for 3 months.