1. This study investigates the effects of the nitric oxide donors on lipopolysaccharide-induced fever in rabbits, and the effect of brain nitric oxide synthase inhibition on the febrile response in pyrogen tolerant animals. 2. The febrile response was reduced by intravenous injections of the nitric oxide donors molsidomine (1.0 mg/kg) and isosorbide dinitrate (0.5 mg/kg) 60 min after intravenous treatment with lipopolysaccharide. 3. The magnitude of fever was also attenuated by intracerebroventricular administration of molsidomine (75 micrograms). 4. Intracerebroventricular pretreatment with the nitric oxide synthase inhibitor, NG-nitro-L-arginine (100 micrograms) 10 min before the injection of lipopolysaccharide significantly enhanced the febrile response in pyrogen tolerant animals. 5. The results suggest that nitric oxide is involved in the central mechanisms of thermoregulation during fever as one of the effective endogenous antipyretics.