This study was designed to test the tumor necrosis factor (TNF) WEHI 164 clone 13 bioassay and the interleukin 6 (IL-6) B9 bioassay for sensitivity to endogenously produced dog TNF and IL-6 and then to use these assays to examine the associations between these cytokines and lipopolysaccharide (LPS)-induced fever. When dogs were injected with LPS (40, 10, 1, 0.1, and 0.01 microgram/kg), the resulting fever was dose dependent. A plot of plasma cytokine changes over time following LPS injections showed that the plasma TNF-like activity appeared to increase in an all-or-none dose response, whereas the increase in plasma IL-6-like activity appeared to be log dose dependent. Plasma TNF-like and IL-6-like activity were then separately plotted against temperature change (fever). Statistical analysis supported the interpretation that both TNF-like and IL-6-like activity were related to LPS-fever in an all-or-none manner, with IL-6 having a threshold region. We conclude that if these cytokines are circulating mediators of fever, they may induce fever in an all-or-none fashion.