Hyperammonemia is a well-recognized metabolic abnormality which occurs in cirrhotic patients with advanced liver dysfunction. We recently documented that hyperglucagonemia that occurs as a result of hepatic glycogen depletion may be responsible for this hyperammonemia by promoting gluconeogenesis to provide glucose as a fuel for functioning of several organ systems. Thus, hepatic glycogen depletion may be the initial process responsible for hyperammonemia. Since the glucose rise following intravenous glucagon administration is a reflection of hepatic glycogen breakdown, we studied the effect of glucagon (1 mg) injection on plasma glucose, insulin and ammonia levels after an overnight fast in cirrhotic patients and normal subjects. Glucose rise was significantly stunted, and ammonia rise was significantly greater in patients with advanced liver dysfunction as compared to normal subjects. Furthermore, the smaller the glucose increment, the earlier the ammonia rise. The smallest glucose responses were seen in the patients with the highest basal plasma ammonia levels. Finally, significant negative relationships were noted between the glucose response to glucagon administration (δglucose) and the degree of liver dysfunction as reflected by Composite Clinical Laboratory Index, as well as basal ammonia and ammonia responses (Δam-monia) on the other. Therefore, this study suggests that hepatic glycogen depletion may be the initial event leading to elevated plasma ammonia concentrations in hepatic cirrhosis.