Over the last three decades, experiments in several mammalian species have shown that the febrile response to bacterial endotoxin is attenuated late in pregnancy. More recent evidence has established that the expression of nitric oxide synthase (NOS) enzymes is increased in the brain late in pregnancy. The current study investigated the possible role of brain nitric oxide in mediating the phenomenon of fever suppression. Core body temperature (T_b) of near-term pregnant rats (day 19-20) was measured following inhibition of brain NOS and intraperitoneal (IP) injection of lipopolysaccharide (LPS, 50µg/kg), they were compared to both day 15 pregnant and virgin animals. Intracerebroventricular (ICV) injection with an inhibitor of NOS, N^G-monomethyl L-arginine citrate (L-NMMA, 280µg), in near-term pregnant rats restored the febrile response to LPS. As expected, near-term dams that received ICV vehicle + IP LPS did not increase Tb, in contrast to the 1.0 ± 0.2°C rise in T_b in dams treated with ICV L-NMMA + IP LPS (p<0.01). In virgin females and day 15 pregnant controls receiving this treatment, the increases in T_b were 1.5 ± 0.3°C and 1.6 ± 0.4°C, respectively. Thus, blockade of brain NOS restored the febrile response to LPS in near-term dams; at 5h post-injection T_b was 60-70% of that observed in virgins and day 15 pregnant animals. ICV L-NMMA alone did not induce a significant change in T_b in any group. These results suggest that the mechanism underlying the suppression of the febrile response in near-term pregnancy is mediated by NO signalling in the brain.