Chronic heart failure (HF) is associated with insulin resistance. Putative mechanisms of insulin resistance are abnormal skeletal muscle blood flow and antagonism of insulin action due to sympathetic nervous system activation. We measured insulin sensitivity, the vasoactive properties of insulin, and the association between insulin resistance and markers of neurohormonal activation in 10 patients with chronic HF and in 9 healthy controls. Noninvasive hemodynamic measurements and an hyperinsulinemic, euglycemic clamp were used. Patients were insulin resistant compared with the controls (p <0.05 for area under insulin dose-response curve). Insulin infusion led to a selective increase in forearm blood flow accompanied by a decrease in mean arterial pressure and superior mesenteric blood flow. Heart rate decreased in patients but not in controls; however, when baseline measurements were controlled for, there was no difference in the overall hemodynamic response to insulin infusion between the study groups. In univariate analysis, age, serum creatinine, fasting insulin, and triglyceride levels correlated inversely with insulin sensitivity (p <0.05 for all). Cardiac output had a significant correlation with insulin sensitivity (p <0.05). On stepwise multiple linear regression analysis, only age and fasting plasma insulin emerged as significant predictors of insulin sensitivity (R(2) 0.613, p = 0.001). In particular, we found no evidence of a relation between insulin sensitivity and plasma noradrenaline. Patients with chronic HF exhibit significant metabolic insulin resistance. Insulin resistance is not secondary to failure of insulin-mediated vasodilatation or sympathetic nervous system activation and is likely due to abnormalities at the level of the skeletal myocyte.