Since the secretion of pancreatic glucagon is largely influenced by changes in the blood glucose level, the response of extrapancreatic glucagon to glycemic changes was investigated in man and dogs. Neither insulin-induced hypoglycemia nor arginine infusion caused a rise in plasma glucagon in two patients with total pancreatectomy, but plasma glucagon increased transiently in one of the two patients after oral glucose load. Glucose-induced hyperglycemia did not alter plasma glucagon in the portal vein in a group of 4 depancreatized dogs. When blood glucose fell lower than 50 mg/100 ml after insulin infusion in a group of 7 depancreatized dogs, plasma glucagon in the portal vein did not increase significantly. The administration of 2-deoxyglucose did not cause any changes in plasma glucagon in the portal vein in a group of 5 pancreatectomized dogs. After the ligation of the hepatic artery, blood glucose decreased gradually in a group of 5 pancreatectomized dogs with portacaval shunt, but plasma glucagon in the vena cava was not altered significantly. It is concluded from the present study that regulation of extrapancreatic glucagon differs from that of pancreatic glucagon.