Effects of endotoxin on carbohydrate metabolism were studied in A/HeJ (endotoxin-sensitive) and C3H/HeJ (endotoxin-resistant) inbred mice. A/HeJ mice developed hypoglycemia within two hours after endotoxin injection, yet liver glycogen content did not differ from controls. Similarly treated C3H/HeJ mice did not develop significant hypoglycemia. Administration of glucagon to endotoxin-treated A/HeJ mice failed to elevate their blood glucose concentrations, while endotoxin-treated mice of the same strain did respond to dibutyryl cyclic AMP with a significant elevation of blood glucose. C3H/HeJ mice on the other hand responded to glucagon and dibutyryl cyclic AMP with elevated blood glucose. Endotoxin-treated C3H/HeJ but not A/HeJ mice were able to carry out gluconeogenesis induced by prednisolone, while both inbred strains showed active glycogenesis after administration of an exogenous glucose load. Administration of glucagon resulted in diminished liver glycogen concentrations in A/HeJ endotoxin-treated mice suggesting no impairment of glycogenolysis. The inability of endotoxin-treated A/HeJ mice to respond to glucagon could be due to impairment of gluconeogenesis. Although endotoxin interfered with the capacity of both inbred strains to respond to glucagon administration with elevation of liver cyclic AMP, the effect was significantly more severe in A/HeJ mice. The susceptibility of A/HeJ mice to the lethal effect of endotoxin may be related to the apparent sensitivity of carbohydrate metabolic pathways to disturbance by endotoxin.