Ciglitazone (5-4-(1-methylcyclohexyfmethoxy)benzyl-thiazolidine-2,4-dione) is a hypoglycemic agent, which has been shown to improve blood glucose levels and in vitro insulin sensitivity in some genetically hyperglycemic rodents. Whether ciglitazone administration prevents the widespread peripheral insulin resistance induced by high fat feeding (HFF) of rats was examined. Insulin action (euglycemic clamp at 150 mU/L insulin, plus 3H-2-deoxyglucose tracer administration) was studied after 3 weeks on diet in control (high carbohydrate fed [HCF]) and HFF rats with or without a ciglitazone gavage (140 mg/k/d) for six days prior to study. HFF reduced the glucose infusion rate required to maintain euglycemia to 57% of control (P less than .01), but this was restored to 82% of control by ciglitazone treatment (P less than .01 v HFF alone). Estimated glucose disposal (Rd) and skeletal muscle glucose metabolic index (Rg', from accumulation of phosphorylated deoxyglucose) were reduced by HFF but restored to control values by concomitant ciglitazone treatment. Ciglitazone increased muscle Rg' by approximately twofold v HFF in all eight muscles sampled. However, in other tissues (white and brown adipose tissue, lung, and heart), ciglitazone did not alter responses from HFF alone. Thus, ciglitazone counteracts whole body insulin resistance in the HFF rat model mainly due to potent effects on insulin action in both oxidative and glycolytic skeletal muscle.