The action of glucagon, epinephrine and cyanide on hepatic glycogen catabolism in meal-fed rats and the corresponding controls was investigated using the isolated perfused liver. The amounts of glycogen catabolites (glucose, L-lactate and pyruvate) released were correlated with the glycogen content of the livers at the different times after feeding. Irrespective of the metabolic condition, the sensitivity of glycogenolysis to glucagon was roughly proportional to the glycogen content of the livers. However, glycogenolysis in livers from meal-fed rats was less sensitive to epinephrine and cyanide. The difference between meal-fed and controls (ad libitum-fed) was particularly pronounced at 22 hours after feeding. It was concluded that resistance to hepatic glycogen depletion in meal-fed rats during the fasting period may be, partly at least, the consequence of a reduced sensitivity of glycogenolysis to epinephrine and to situations of reduced rates of oxidative phosphorylation.