The purpose of the current study was to explore the effects of N-methyl-D-aspartate (NMDA)-receptor antagonists (MK-801 and LY235959) administered intracerebroventricularly on the changes of both core temperature and hypothalamic levels of 2,3-dihydroxybenzoic acid (2,3-DHBA) induced by intracerebroventricular injection of glutamate (100 – 400 μg at 10 μl/rabbit) or intravenous administration of lipopolysaccharide (LPS) (2 μg/kg) in rabbits. The measurements of 2,3-DHBA were used as an index of the intrahypothalamic levels of hydroxyl radicals. The rise in both the core temperature and hypothalamic 2,3-DHBA could be induced by intracerebroventricular injection of glutamate or intravenous administration of LPS. The glutamate- or LPS-induced fever and increased hypothalamic levels of 2,3-DHBA were significantly antagonized by pretreatment with injection of MK-801 or LY235959 1 h before glutamate or LPS injection. The increased levels of prostaglandin E₂ in the hypothalamus induced by glutamate or LPS could be suppressed by MK-801 or LY235959. The data demonstrate that prior antagonism of NMDA receptors in the brain, in addition to reducing prostaglandin E₂ production in the hypothalamus, suppresses both the glutamate- and LPS-induced fever and increased hypothalamic hydroxyl radicals.