Phagocytic cells contain NADPH oxidase that they use for host defense by catalyzing the production of superoxide. Bacterial lipopolysaccharide (LPS) has been found to stimulate NADPH oxidase in mobile and sessile macrophages and microglia. It also evokes fever in homeothermic animals and men, a reaction mediated by central nervous system (CNS) activities. The purpose of the present study was to determine whether reactive oxygen species are involved in LPS-induced fever. In rabbits we found that plasma hydroperoxide levels increased and catalase activity decreased 15 min after LPS injection and that fever started with a similar latency, while plasma levels of tumor necrosis factor-α (TNFα) increased 30 min after the injection. Treating rabbits with methylene blue or aspirin did not affect TNFα secretion but prevented the LPS-induced rise of hydroperoxides and the inactivation of catalase, abolishing fever. Incubation of human blood with nitroblue tetrazolium and LPS increased the number of formazan-positive neutrophils from 10 ± 5 to 52 ± 9%. Adding LPS to blood preincubated with either methylene blue, α-lipoic acid, or aspirin respectively decreased the number of formazan-positive neutrophils to 0.9 ± 0.8, 0.8 ± 0.9, or 2.0 ± 0.9%, disclosing the antioxidant capacity of these drugs. Systemic application of 80 mg/kg α-lipoic acid elicited heat-loss reactions within 15 min and decreased core temperature by 2.2 ± 0.3°C within 2 h. α-Lipoic acid applied 45 min after LPS induced antipyresis within 15 min, and this antipyresis was associated with a decrease of elevated hydroperoxide levels and restoration of catalase activity. Our results show that fever is prevented when the production of reactive oxygen species is blocked and that an elevated body temperature returns to normal when oxygen radical production decreases. Estimation of plasma dihydrolipoic acid (DHLA) levels following injection of 80 mg/kg α-lipoic acid in afebrile and febrile rabbits revealed that this acid is converted into DHLA, which in afebrile rabbits increased the plasma DHLA concentration from 2.22 ± 0.26 μg/ml to peak values of 8.60 ± 2.28 μg/ml DHLA within 30 min and which in febrile rabbits increased it from 0.84 ± 0.22 μg/ml to peak values of 3.90 ± 0.94 μg/ml within 15 min. Methylene blue, aspirin, and α-lipoic acid, which all cross the blood–brain barrier, seem to act not only on peripheral tissues but also on the CNS. Brain structures that have been shown to sense oxidative stress are vicinal thiol groups attached to the NMDA subtype of glutamate receptor. Their reduction by thiol-reducing drugs like dithiothreitol or DHLA has been found to increase glutamate-mediated neuronal excitability, while the opposite effect has been observed after their oxidation. Because we found that systemic application of α-lipoic acid in the afebrile state elicits hypothermia and in the febrile state is antipyretic, we think this type of NMDA receptor is involved in thermoregulation and that oxidation of its thiol groups induces fever. It appears that temperature homeostasis can be maintained only if the redox homeostasis of the brain is guaranteed.