The purpose of these studies was to assess whether interleukin 6 (IL-6) is an endogenous pyrogen, responsible for all or part of the fever caused by lipopolysaccharide (LPS) in rats. We have found that the core temperature (as measured by biotelemetry) rose significantly after intracerebroventricular (icv) injection of recombinant human IL-6. The same doses of IL-6, when administered intravenously or intraperitoneally, had no effect on body temperature. The fever caused by icv administration of IL-6 was completely blocked by indomethacin. After injection of fever-inducing doses of LPS, the plasma and cerebrospinal fluid (CSF) IL-6 activities rose, the former much more than the latter. The correlation between fever and plasma IL-6 activity was r = 0.84 (P less than 0.0025); the correlation between fever and CSF IL-6 activity was r = 0.77 (P less than 0.015). The results of this study are consistent with the hypothesis that IL-6 is a mediator of LPS-induced fever in the rat.