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 (Tb) of near-term pregnant rats ( day 19 and 20) was measured following inhibition of brain NOS and intraperitoneal injection of LPS (50 μg/kg); they were compared with both day 15 pregnant and virgin animals. Intracerebroventricular injection with an inhibitor of NOS, NG-monomethyl-l-arginine citrate (l-NMMA; 280 μg), in near-term pregnant rats restored the febrile response to LPS. As expected, near-term dams that received intracerebroventricular vehicle + IP LPS did not increase Tb, in contrast to the 1.0 ± 0.2°C rise in Tb 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 Tb 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 5 h postinjection, Tb was 60–70% of that observed in virgins and day 15 pregnant animals. Intracerebroventricular l-NMMA alone did not induce a significant change in Tb in any group. These results suggest that the mechanism underlying the suppression of the febrile response in near-term pregnancy is mediated by nitric oxide signaling in the brain.