Recombinant tumor necrosis factor (TNF) had hypothermic activity in vivo. Intravenous injection of TNF resulted in a hypothermic reaction of mice within 3 to 6 hours. This reaction was not the result of interleukin 1 (IL1) release from macrophages/monocytes. Peritoneal exudate cell cultures from endotoxin low responder mice or human peripheral mononuclear leukocyte cultures did not generate IL1 activity in the supernatant after exposure to TNF. The addition of interferon-gamma (IFN-gamma) or preexposure to IFN-gamma and then stimulation with TNF did also not result in IL1 secretion. No IL1 inhibitor was generated and TNF did not interfere with the IL1 test systems. Therefore, we conclude that the hypothermic activity of TNF is not mediated via the induction of IL1 production by mononuclear phagocytes.