Tumor necrosis factor α (TNF-α) is a cytokine that is responsible, in part, for several aspects of the acute-phase response to inflammation, including the generation of fever. TNF-α has direct effects on central nervous system neurons deep within the hypothalamus that are involved in producing the febrile response, but the blood-brain barrier prevents circulating TNF-α from having access to these sites. We therefore have hypothesized that TNF-α may be produced in the brain and used as a mediator in the cerebral components of the acute-phase response. We used in situ hybridization to determine the distribution of production of TNF-α mRNA in the mouse brain after systemic administration of lipopolysaccharide. During the initial phase of fever, hybridization was observed in perivascular cells and neurons in circumventricular organs, including the vascular organ of the lamina terminalis, median eminence, and area postrema, as well as along the ventral surface of the medulla; hybridization was also prominent over many cell in the meninges. During the late phase of the response, hybridization was observed over neurons in the pericircumventricular nuclei such as the anteroventral periventricular and arcuate nuclei of the hypothalamus and the nucleus of the solitary tract. TNF-α produced by a cascade of neurons within the brain may participate in the complex autonomic, neuroendocrine, metabolic, and behavioral responses to infection and inflammation.