Infusion of glucose into the hepatic artery blocks the stimulatory effect of the "portal signal" on net hepatic glucose uptake (NHGU) during portal glucose delivery. We hypothesized that hepatic artery ligation (HAL) would result in enhanced NHGU during peripheral glucose infusion because the arterial glucose concentration would be perceived as lower than that in the portal vein. Fourteen dogs underwent HAL ~16 d before study. Conscious 42-h-fasted dogs received somatostatin, intraportal insulin and glucagon infusions at 4-fold basal and basal rates, respectively, and peripheral glucose infusion to create hyperglycemia. After 90 min (period 1), 7 dogs (HALpo) received intraportal glucose (3.8 mg^.kg^-1.min^-1) and 7 (HALpe) continued to receive only peripheral glucose for 90 min (period 2). These 2 groups were compared to 9 non-HAL control dogs (Control) treated as were HALpe. During period 2, the arterial plasma insulin concentrations (24±3, 20±1, and 24±2 µU/ml) and hepatic glucose loads (39.1±2.5, 43.8±2.9, and 37.7±3.7 mg^.kg^-1.min^-1) were not different in HALpe, HALpo, and Control, respectively. HALpo exhibited greater (P<0.05) NHGU than HALpe and Control (3.1±0.3, 2.0±0.4, and 2.0±0.1 mg^.kg^-1.min^-1, respectively). Net hepatic carbon retention was ~2-fold greater (P<0.05) in HALpo than in HALpe and Control. NHGU and net hepatic glycogen synthesis during peripheral glucose infusion were not enhanced by HAL. Even though there exists an intrahepatic arterial reference site for the portal vein glucose concentration, the failure of hepatic artery ligation to result in enhanced NHGU during peripheral glucose infusion suggests the existence of one or more comparison sites outside the liver.