We tested the effects of tumor necrosis factor (TNF) soluble receptor (sTNFR) and anti-TNF serum (anti-TNF) administered intraperitoneally on fever induced by lipopolysaccharide (LPS) in mice. Both agents have been shown to block bioactivity of mouse TNF-alpha. Core temperature (Tb) and locomotor activity in unrestrained mice were measured by biotelemetry. Within 1 h from the LPS injection (2.5 mg/kg ip) Tb decreased below normal for 5-6 h and motor activity was depressed for the following 48 h. After this initial reduction, Tb increased and reached a peak at approximately 24 h postinjection. Anti-TNF and sTNFR blocked this "hypothermic phase" after LPS, and the fevers started sooner; however, the levels and time of peak temperature did not change markedly. In addition, a human recombinant TNF-alpha given intraperitoneally abolished fever and prolonged the fall of Tb in mice after LPS. We conclude that the reduction of Tb soon after injection of LPS in mice is dependent on TNF-alpha.