The hemodynamic concept of insulin resistance assumes that vasodilatory effects of insulin determine glucose uptake. Sickle cell disease (SCD) is characterized by microangiopathy and microvascular occlusion. Therefore, we hypothesized that patients with SCD have a reduced insulin-mediated glucose uptake. In 8 patients with SCD and 8 matched normal controls, we studied the effects of a 4-hour insulin infusion (50 mU/kg/h) on glucose uptake and leg blood flow (LBF) using the euglycemic clamp technique and venous occlusion plethysmography. Time-control experiments were performed in the same subjects. Insulin-mediated glucose uptake (M value, mg/kg/min) did not differ between patients with SCD and control subjects during the second (6.3 ± 4.6 and 7.6 ± 2.6, P = .5), third (7.5 ± 4.6 and 9.3 ± 3.4, P = .4) and fourth hour (8.6 ± 4.7 and 11.0 ± 2.9, P = .2) of the clamp. At baseline, LBF was higher in the patients with SCD than in the controls (3.28 ± 1.68 and 1.37 ± 0.47 mL/min/dL, respectively; P = .005). Insulin-induced increases in LBF in patients with SCD and in normal subjects were not different (P = .9). Respectively, 56% and 24% of the changes in glucose uptake could be explained from changes in LBF in the course of the insulin infusion in the patients with SCD and controls. We suppose that the comparable insulin sensitivity between both groups is due to a compensatory hemodynamic state in SCD characterized by vasodilation and increased flow.