This study was undertaken to evaluate the hypoglycemic effects of endotoxin in C3H/HeJ (nonresponder) mice. Endotoxin from Salmonella enteritidis ser Typhimurium strain SR-11 was used and the median lethal dosed (LD50) for random-outbred Swiss-Webster mice and C3H/HeJ mice were 450 microgram and 3,000 microgram, respectively. At intervals after intraperitoneal injection of endotoxin (1 LD50) animals were killed, and blood glucose, liver glucose, and liver glycogen levels were killed, and blood glucose, liver glucose, and liver glycogen levels were measured. The time course of carbohydrate depletion in both strains of mice was almost identical. Little change from controls was noted, however, in nonresponder mice given the LD50 dose for normal responder mice. Passive transfer of plasma from C3H/HeJ mice appeared to protect conventional responder mice from the carbohydrate-depleting effects of endotoxin; whereas, passive transfer of peritoneal cells from C3HeB/FeJ responder mice to nonresponders appeared to sensitize C3H/HeJ mice to this effect. In order to evaluate clearance and detoxification of endotoxin in non-responder mice, 14 C-labeled lipopolysaccharide was prepared from bacteria grown in broth containing D-glucose-14 C(U). Mice were injected intravenously with labeled endotoxin, and blood, liver, spleen, kidney, heart, lung, and brain were counted for radioactivity at intervals after injection. Results from these tracer studies indicate that the clearance of lipopolysaccharide in nonresponder mice is slower than that seen in conventional animals. The results of this study further support the suggestion that endotoxin exerts its effects on carbohydrate metabolism via mediators resulting from endotoxin-cell surface interactions.