Tumor necrosis factor alpha (TNF alpha) was repeatedly microinfused into the lateral ventricle of guinea pig brains at a dose of 200 ng, 4 times within 150 min, at intervals of 3 days. In comparison to guinea pigs infused with solvent according to the same time schedule. the animals responded to TNF alpha with pronounced fevers. The quantity of the fever response was the same after each of the 4 microinfusions of TNF alpha. Three days after the last infusion of TNF alpha or solvent all animals received an intramuscular injection of bacterial lipopolysaccharide (LPS). The fever in response to LPS was the same in both groups. Thus, the reported development of tolerance to repeated systemic administration of TNF alpha 1-3 does not develop inside the blood-brain barrier. Also, the febrile response to LPS is not influenced by repeated central pre-treatment with TNF alpha, whereas repeated peripheral treatment does have an effect.