The concentrations of insulin and glucagon were measured in the portal and hepatic vein, the abdominal aorta and caval vein in the rat during a normal 24-h feeding cycle. Portal insulin levels showed little diurnal variation while hepatovenous and peripheral values were clearly increased during the eating phase. Conversely, portal glucagon levels were maximal during the fasting period while hepatovenous and peripheral concentrations showed little diurnal variation. The removal of insulin and glucagon by the liver was not constant, but independently regulated. During meals the liver increased the high portal insulin/glucagon ratio further to an even higher peripheral ratio favouring glucose utilization, e.g. by muscle and adipose tissue. During a short fast the liver decreased the low portal insulin/glucagon ratio further to an even lower peripheral ratio leading to glucose saving, e.g. by muscle and adipose tissue in favour of the brain and erythrocytes. The results indicate that the liver has an important role in the regulation of peripheral insulin/glucagon levels.