Nonlethal endotoxemia was produced in conscious fasted rats by the intravenous (iv) administration of Salmonella enteritidis lipopolysaccharide (LPS) at a dose of 30 micrograms/100 g together with the typical acute-phase response of fever at 4 hr post-LPS. Also at 4 hr post-LPS both hyperinsulinemia and hyperglucagonemia were manifested, the (insulin: glucagon)(I: G) molar ratio was not different from saline control animals, and normoglycemia was maintained. The monokine interleukin-1 (IL-1), which is synthesized de novo and then released by macrophages and monocytes following LPS phagocytosis, has been implicated in the typical responses to endotoxemia. Therefore, human natural IL-1 was injected iv at a dose of 50 U into conscious fasted rats. IL-1-induced fever occurred at 30 min postinjection. Hyperinsulinemia equal to two times the saline control value was also present at 30 min after monokine injection, with plasma insulin levels declining to below control values by 60 min and remaining depressed for up to 12 hr. In contrast, plasma glucagon concentrations were not significantly altered at any time between 15 min and 12 hr post-IL-1. Despite IL-1-elicited hyperinsulinemia with unchanged glucagon, which elevated the I: G molar ratio, normoglycemia was maintained after monokine administration. The coincident onset of fever and hyperinsulinemia at 30 min after iv administration of IL-1 suggests a common mediator for both responses.