Troglitazone is a newly developed antidiabetic agent that shows hypoglycemic effects in insulin-resistant animal models and non-insulin-dependent diabetic humans. To determine whether this drug could affect in vivo insulin action acutely, insulin-stimulated glucose utilization was measured with the euglycemic glucose clamp technique before, during, and after troglitazone infusion (20 μg/min) in normal rats. Hepatic glucose production (HGP) was measured with a tracer-dilution technique (d-[3-³H]-glucose). At 18-pmol/kg/min insulin infusion rate, steady-state glucose disposal rate (GDR) was significantly increased during troglitazone infusion versus control vehicle infusion (162 ± 6.1 v 142.3 ± 4.4 μmol/kg/min, P < .02). The glucose infusion rate (GIR) required to maintain euglycemia increased shortly (10 to 20 minutes) after initiation of troglitazone infusion and was significantly greater until 30 minutes after cessation of the drug versus the vehicle infusion. At 9-pmol/kg/min insulin infusion rate, HGP was significantly decreased during troglitazone infusion as compared with control vehicle infusion (21.7 ± 3.5 v 39.5 ± 3.7 μmol/kg/min, P < .02). These results indicate that troglitazone can acutely increase in vivo insulin action in normal rats, and some possible mechanisms are discussed.