Diabetic patients treated with inhaled insulin exhibit reduced fasting plasma glucose levels. In dogs, insulin action in muscle is enhanced for as long as 3 h after insulin inhalation. This study was designed to determine whether this effect lasts for a prolonged duration such that it could explain the effect observed in diabetic patients. Human insulin was administered via inhalation (Exubera; n = 9) or infusion (Humulin R; n = 9) in dogs using an infusion algorithm that yielded matched plasma insulin kinetics between the two groups. Somatostatin was infused to prevent insulin secretion, and glucagon was infused to replace basal plasma levels of the hormone. Glucose was infused into the portal vein at 4 mg/kg/min and into a peripheral vein to maintain the arterial plasma glucose level at 160 mg/dl. Arterial and hepatic sinusoidal insulin and glucose levels were virtually identical in the two groups. Notwithstanding, glucose utilization was greater when insulin was administered by inhalation. At its peak, the peripheral glucose infusion rate was 4 mg/kg/min greater in the inhalation group, and a 50% difference between groups persisted over 8 h. Inhalation of insulin caused a greater increase in nonhepatic glucose uptake in the first 3 h after inhalation; thereafter, net hepatic glucose uptake was greater. Inhalation of insulin was associated with greater than expected (based on insulin levels) glucose disposal. This may explain the reduced fasting glucose concentrations observed in humans after administration of certain inhaled insulin formulations compared with subcutaneous insulin.