To test the hypothesis that brain to blood clearance is a mechanism by which brain inflammation and damage can increase circulating acute phase cytokines, rate of transfer of [<sup>125</sup>I]-tumor necrosis factor-α ([<sup>125</sup>I]-TNF) from brain to blood was determined. Acid precipitable [<sup>125</sup>I]-TNF appeared in peripheral blood within 5 min of intracerebroventricular (i.c.v.) injection and was cleared from brain to blood following first order kinetics at a fractional rate of 0.01123 ± 0.0030/min, a value virtually identical with a previously determined clearance rate of [<sup>125</sup>I]-IL-6. Area under blood concentration curve compared with that after intravenous injection shows that 31.6 ± 5.8% of the intracerebral dose reached peripheral blood in 4 h. Elevated ratios of superior sagittal sinus to aortic blood radioactivity concentration at 1 and 3 h (1.48 ± 0.26, p = 0.042; 1.95 ± 0.39, p = 0.026, respectively) indicate that TNF-α drains from brain at least in part via the sagittal sinus. Escherichia coli lipopolysaccharide i.c.v. injection increased the rate of brain efflux of TNF-α.