Tissue sensitivity to insulin was examined in 36 control subjects and 19 insulin-dependent diabetics with diabetes of long-standing duration (mean = 10 ± 3 yr) employing the insulin clamp technique (Δ plasma insulin concentration ∼100 βU/ml). Eleven of the diabetics (group I) were studied at their fasting hyperglycemic level (173 mg/dl); the remaining 8 diabetics (group II) were studied after lowering their plasma glucose concentration to euglycemic levels (90 mg/dl). Despite plasma glucose levels that were almost twice as great in the diabetics (group 1,173 versus 91 mg/dl, P < 0.001), insulin-mediated glucose metabolism, 4.77 ± 0.18 mg/kg · min, was reduced by 32% versus controls, 7.03 ± 0.22 mg/kg · min (P < 0.01). When the control subjects were restudied at plasma glucose levels (166 ± 2 mg/dl) that were comparable to those of the diabetics, insulin-mediated glucose metabolism was 12.14 ± 0.96 mg/kg · min (P < 0.01). In diabetics studied at euglycemic levels (group II) insulin-mediated glucose metabolism, 3.39 ± 0.30 mg/kg · min, was reduced even further. The metabolic clearance rate in the 19 diabetics, 3.31 ± 0.23 mg/kg · min, was reduced by 58% compared with controls, 7.83 / 0.25 (P < 0.001). These results emphasize the severe degree of insulin resistance that exists in the insulin-dependent diabetics. Basal hepatic glucose production in the diabetic group, 2.96 ± 0.24 mg/kg · min, was 26% greater than in the controls, 2.35 ± 0.04 (P < 0.001). The fasting plasma glucose concentration displayed a strong positive correlation (r = 0.857, P < 0.001) with basal hepatic glucose production and was weakly and inversely correlated (r = −0.413, P = 0.07) with the basal glucose clearance. Following hyperinsulinemia, however, suppression of hepatic glucose production was ∼ 9 5% in both diabetics and controls, suggesting that peripheral tissues are primarily responsible for the observed impairment in insulin-mediated glucose uptake. The present results indicate that impaired insulin action is a common feature of insulin-dependent diabetics, despite daily insulin requirements (35 ± 2 U/day) that would not clinically characterize them as being insulin resistant.