Insulin resistance is associated with hypertension, obesity, dyslipidemia, and type 2 diabetes. It is well known that tumor necrosis factor (TNF)-α is one of the factors linked to obesity-induced insulin resistance; however, there have been no reports on the role of TNF-α in insulin resistance in nonobese insulin-resistant hypertensives. We tested the hypothesis that TNF-α affects insulin resistance in nonobese insulin-resistant hypertensive fructose-fed rats (FFR) and that a TNF-α–converting enzyme (TACE) inhibitor that blocks TNF-α secretion improves insulin resistance in FFR. Six-week-old male Sprague-Dawley rats were fed either standard chow (control) or fructose-rich chow (FFR) for 6 weeks. For the last two weeks of a six-week period of either diet, the rats were treated with a vehicle (control or FFR) or a TACE inhibitor (100 mg/kg/d of KB-R7785; FFR+TACE-I) in peritoneal injection. At the age of 12 weeks, insulin sensitivity was assessed in all conscious rats by the euglycemic hyperinsulinemic glucose clamp technique. While FFR had higher blood pressure than the control rats ( P <0.01), the TACE inhibitor did not change blood pressure. Insulin sensitivity (M-value) was reduced in FFR compared with that in the control rats (16.7±1.1 mg/kg per min and 10.3±0.6 mg/kg per min in the control rats and FFR, respectively, P <0.001), and the TACE inhibitor improved insulin sensitivity to the level of the control rats (14.3±1.2 mg/kg per min in FFR+TACE-I, P <0.01). These data indicate that TNF-α plays a major role in insulin resistance in nonobese insulin-resistant models and also suggest that TACE would be a good target for controlling insulin resistance not only in obese models but also in nonobese insulin-resistant models.