Troglitazone is a new orally active hypoglycemic agent that has been shown to reduce insulin resistance and hyperinsulinemia in both diabetic animal models and non-insulin-dependent diabetes mellitus (NIDDM) subjects. To determine whether this drug could prevent the development of fructose-induced insulin resistance and related abnormalities, we studied the effects of troglitazone on the insulin resistance induced by fructose feeding in rats. Normal male Sprague-Dawley rats were fed a high-fructose diet for 3 weeks with and without troglitazone as a food admixture (0.2%) or were fed normal chow to serve as a control group. In vivo insulin resistnace was measured by the euglycemic hyperinsulinemic clamp technique at two different insulin infusion rates, 29 (submaximal stimulation) and 290 (maximal stimulation) pmol.kg⁻¹ · min⁻¹. Fructose feeding markedly reduced submaximal glucose disposal rate (GDR) (113.8 ± 8.3 vs. 176.0 ± 5.6 µmol.kg⁻¹ · min⁻¹ P < 0.05) and maximal GDR (255.9 ± 5.6 vs. 313.6 ± 10.5 µmol.kg⁻¹ · min⁻¹ P < 0.05), reduced the suppressibility of submaximal hepatic glucose production (HGP; 45.5 ± 5.0 vs. 11.7 ± 5.0 µmol.kg⁻¹ · min⁻¹ P < 0.05), and resulted in hypertriglyceridemia and hypertension. Troglitazone treatment completely restored the GDR (submaximal 158.2 ± 5.6, maximal 305.3 ± 6.1 µmol.kg⁻¹ · min⁻¹) and submaximal HGP (9.4 ± 2.8 µmol.kg⁻¹ · min⁻¹) to control levels and also normalized the elevated plasma triglyceride concentration and systolic blood pressure levels in fructose-fed rats. These results suggest that troglitazone treatment could completely prevent the insulin resistance, hypertension, and hypertriglyceridemia induced by a diet high in fructose and that the drug might prove useful in the treatment and/or prevention of nonhyperglycemic insulin-resistant states as well as in the treatment of established NIDDM.