Inhibition of tumor necrosis factor (TNF)-α results in a marked increase in insulin sensitivity in obese rodents. We investigated the influence of a TNF antagonist [Ro 45-2081, a recombinant fusion protein that consists of the soluble TNF-receptor (p55) linked to the Fc portion of human IgG1] on insulin sensitivity of patients with android obesity. Seven patients (five women and two men; mean ± sd age, 41 ± 4 yr; body mass index, 36.1 ± 4.7 kg/m²; waist to hip ratio, 0.99 ± 0.11) were studied (three patients with normal glucose tolerance and four patients with impaired glucose tolerance or mild diabetes; all were hyperinsulinemic). Each patient underwent two consecutive euglycemic hyperinsulinemic glucose-clamp tests: 48 h after injection of placebo and 48 h after a single iv injection of 50 mg Ro 45-2081. In both tests, steady-state plasma glucose and insulin levels were similar. Insulin-mediated glucose disposal (2.23 ± 0.74 vs. 2.38 ± 0.99 mg/kg⁻¹·min⁻¹) and glucose metabolic clearance rate (2.28 ± 0.85 vs. 2.48 ± 1.03 mL/kg⁻¹·min⁻¹) were similar after placebo and after the drug. Indirect calorimetry showed no difference in substrate oxidation rates between the two experimental conditions. In conclusion, under the conditions of this study, no improvement in insulin sensitivity was observed in obese insulin-resistant patients following a single iv administration of a recombinant TNF receptor: Fc fusion protein.