The lethality of endotoxin is greatly enhanced in lead-sensitized rats. Previous work showed that hepatic carbohydrate metabolism in lead-treated rats is perturbed by minute endotoxin doses [Fed Proc 41:1607, 1982]. These studies were extended to rats made tolerant to endotoxin by IV injection of lipopolysaccharide (50 micrograms/100 g body weight [BW]) 18 h before simultaneous treatment with lead acetate trihydrate (1.5 mg/100 g BW) and endotoxin (1.0 micrograms/100 g BW). Liver samples removed by freeze-clamping at 5 h from fasted young adult male rats were assayed for glycolytic intermediates. The tolerant rats generally showed smaller alterations in concentrations of metabolites than nontolerant comparison rats challenged with lead and endotoxin. However, phosphoenolpyruvate (PEP) levels were similarly elevated (80-90%) in both groups. The failure of the tolerance procedure to minimize or protect against hepatic PEP changes suggests that the enzymes forming or consuming this metabolite were particularly vulnerable to the action of an endotoxin-released mediator. The fact that some liver glycolytic intermediates remain markedly altered despite amelioration of the lethal effects of endotoxin by the tolerance procedure indicates the existence of independent mediators acting on carbohydrate metabolism in the endotoxic rats.