We assessed glucose counterregulation during intensive insulin therapy in 20 patients with insulin-dependent diabetes mellitus (IDDM) by injecting therapeutic doses of regular insulin subcutaneously after overnight maintenance of euglycemia. As compared with nondlabetic controls matched for age and weight, 17 of the patients had more severe and more prolonged hypoglycemla (nadir, 42±2 in patients vs. 60±2 mg per deciliter In controls P<0.01; duration, 6.2±0.4 vs. 2.1±0.6 hours, P<0.01). Most patients had decreased responses of several counterregulatory hormones. Marked rebound hyperglycemia (≈300 mg per deciliter) ultimately developed in 11 patients. The only features distinguishing patients with rebound hyperglycemia from those without it were plasma free insulin concentrations during recovery from hypoglycemia (those with vs. those without, 7± 1 vs. 22±2 μU per milliliter, P<0.01) and insulin-antibody binding (5±1 vs. 30±5 per cent, P<0.01). Rates of plasma glucose recovery from hypoglycemia were inversely correlated with plasma free insulin concentrations (r = -0.84, P<0.01); the latter in turn were directly correlated with insulin-antibody binding (r = 0.94, P<0.01). We conclude that many patients with IDDM have impaired glucose counterregulation due to multiple defects in counterregulatory-hormone secretion. This is associated with Increased insulin-antibody binding, which prolongs the half-life of insulin. In such patients, intensive insulin therapy may be hazardous. (N Engl J Med 1984; 310:1706–11.).