Tumor necrosis factor (TNF)-α may play a role in the insulin resistance of obesity and NIDDM. Troglitazone is a new orally active hypoglycemic agent that has been shown to ameliorate insulin resistance and hyperinsu-linemia in both diabetic animal models and NIDDM subjects. To determine whether this drug could prevent the development of TNF-α-induced insulin resistance, glucose turnover was assessed in rats infused with cytokine and pretreated with troglitazone. Normal male Sprague-Dawley rats were fed normal powdered food with or without troglitazone as a food admixture (0.2%). After ∼10 days, rats were infused with TNF-a for 4–5 days, producing a plasma concentration of 632 ± 30 pg/ml. In vivo insulin action was measured by the euglycemic-hyperinsulinemic clamp technique at a sub-maximal (24 μmol · kg⁻¹ · min⁻¹) and maximal insulin infusion rate (240 μmol · kg⁻¹ · min⁻¹). TNF-α infusion resulted in a pronounced reduction in submaximal insulin-stimulated glucose disposal rate (GDR) (97 ± 10 vs. 141 ± 4 μmol · kg⁻¹ · min⁻¹ P < 0.05), maximal GDR (175 ± 8 vs. 267 ± 6 μmol · kg⁻¹ · min⁻¹ P < 0.01), and in insulin receptor-tyrosine kinase activity (IR-TKA) (248 ± 39 vs. 406 ± 32 pmol ATP/pmol IR, P < 0.05). It also led to a marked increase in basal insulin (90 ± 24 vs. 48 ± 6 pmol/1, P < 0.05) and free fatty acid (FFA) concentration (2.56 ± 0.76 vs. 0.87 ± 0.13 mmol/1, p < 0.01). Troglitazone treatment completely prevented the TNF-α-induced decline in submaximal GDR (133 ± 16 vs. 141 ± 4 umol · kg⁻¹ · min⁻¹, NS) and maximal GDR (271 ± 19 vs. 267 ± 6 μmol · kg¹ · min¹, NS). The hyperlipidemia was partially corrected by troglitazone (1.53 ± 0.28 vs. 0.87 ± 0.13 mmol/1, P < 0.05), while IR-TKA and insulin concentration remained unaffected by the drug. Troglitazone restores insulin action possibly by lowering the FFA concentration of the blood and/or by stimulating glucose uptake at an intracellular point distal to insulin receptor autophosphorylation in muscle. If TNF-α plays a role in the development of the obe-sity/NIDDM syndrome, troglitazone may prove useful in its treatment.