The effect of tumor necrosis factor-alpha (TNF-alpha) on the febrile response to interleukin-1 beta (IL-1 beta) was investigated in rats. While both of these substances are capable of causing fever when injected into rats, an earlier study showed that the injection of antiserum against TNF-alpha enhanced endotoxin [lipopolysaccharide (LPS)] fever, suggesting that physiological levels of circulating TNF may act to limit the magnitude of fever. In the present study, the intraperitoneal injection of 1 microgram/kg of TNF-alpha significantly attenuated the fever due to the intraperitoneal injection of 10 micrograms/kg of IL-1 beta. Higher doses of TNF-alpha (10 and 50 micrograms/kg injected ip) slightly lowered the febrile response to this dose of IL-1 beta, but these changes were not significant. None of these doses of TNF-alpha alone significantly altered body temperature. The injection of 1 microgram/kg of TNF-alpha also significantly lowered the febrile response to the intraperitoneal injection of 10 micrograms/kg of LPS. The febrile responses to the preoptic area (POA) or intraperitoneal injection of IL-1 beta were not changed when a nonpyrogenic dose of TNF-alpha was simultaneously injected into the POA. Further studies are needed, however, before we can conclude that TNF does not act in the central nervous system to control the febrile response. These data support the hypothesis that nonpyrogenic levels of TNF act in the systemic circulation to suppress the development of fever.