Endotoxin-tolerant mice are sensitized to cold (5 degrees C) stress by an injection of 0.4 ml serum collected from zymosan-pretreated mice 2 h after an intravenous (iv) injection of 25 microgram endotoxin. Deaths begin after 6 h and most animals die by 10 h, The factor in serum believed to be responsible for this effect is called glucocorticoid antagonizing factor (GAF). Tolerant mice given 10 microgram endotoxin live for 10 h and two-thirds survive for 24 h. Serum from endotoxin-poisoned conventional mice reduces survival time significantly but not as dramatically as that from zymosan-primed mice. The latter serum, but not endotoxin, causes a rapid drop in the core temperature of tolerant mice housed at 5 degrees C and inhibits the endogenous induction of phosphoenolpyruvate carboxykinase (PEPCK) (EC 4.1.1.32) in tolerant mice exposed for 4--5 h to the cold. An injection of 25 microgram endotoxin does not have this effect on the enzyme. Serum that produces these responses also sensitizes mice to endotoxin lethality and blocks the protection normally afforded against endotoxin by adrenocorticoids.