Lipopolysaccharide (LPS) stimulates peripheral mononuclear cells (PBMC) to synthesize or release pyrogenic cytokines, including interleukin-1β (IL-1β), IL-6, and tumor necrosis factor-alpha (TNF-α). Nuclear factor-kappa B (NF-κB) influences inflammatory responses through the regulation of genes encoding cytokines. In the present study, experiments were carried out to determine whether an inhibition of NF-κB mechanisms causes an inhibition of pyrogenic cytokine synthesis or release from PBMC and results in antipyresis. Intravenous administration of the supernatant fluids obtained from the human PBMC incubated with LPS caused feverlike hyperthermia in rabbits. The febrile responses were in parallel with the levels of IL-1β, IL-6, and TNF-α in supernatant fluids. Both the fever and the increased levels of these cytokines in supernatant fluids were decreased by incubating LPS-PBMC with NF-κB inhibitors, including pyrrolidine dithiocarbamate, sodium pyrithione, N-acetyl-cysteine, and curcumin. Moreover, an intravenous administration of LPS (0.5–2 μg/kg) produced dose-dependent fever in the rabbits. The fevers were in parallel with the levels of IL-1β, IL-6, and TNF-α in rabbit serum. A pretreatment of rabbits with an intravenous injection of pyrrolidine dithiocarbamate, sodium pryithione, N-acetyl-cysteine, or curcumin 1 h before the intravenous administration of LPS significantly attenuated the LPS-induced fever and/or increased levels of these cytokines in the serum of rabbits. Furthermore, pretreatment with an intravenous dose of anti–IL-1β, anti–IL-6, or anti–TNF-α monoclonal antibody significantly attenuated the fever induced by the intravenous injection of LPS in rabbits. The antipyretic effects exerted by anti–L-1β monoclonal antibody were greater than those exerted by anti–L-6 or anti–NF-α monoclonal antibody. The data indicate that NF-κB activation correlates with an LPS-induced synthesis or a release of cytokines (in particular, IL-1β) from PBMC and triggers fever. Blocking NF-κB mechanisms in the PBMC with NF-κB inhibitors may be an effective strategy in the fever therapy.