Soluble receptors for cytokines can be important regulators of cytokine function. By binding to their cytokine ligands, they act as antagonists and carrier proteins. We investigated whether the blood-to-brain saturable transport of human tumor necrosis factor-alpha (TNF) and human interleukin-1 alpha (IL-1) radioactively labeled with 125I could be blocked by preincubation with their soluble receptors. At ratios of 100:1 and 1,000:1 of receptor to cytokine, the soluble p75 human receptor to TNF (rhuTNFR:Fc) totally blocked the entry of human or murine TNF into the brain. However, the soluble murine receptor to IL-1 (muIL-1R) only partially blocked IL-1 entry. Radioactively labeled rhuTNFR:Fc and muIL-1R were not transported across the blood-brain barrier (BBB) and were no more able to penetrate the BBB than the vascular marker serum albumin. This indicates that the transporter at the BBB for IL-1, but not the one for TNF, can strip the cytokine from its soluble receptor. These findings might be useful in determining which, if any, of the actions exerted on the brain by blood-borne cytokines are due to penetration of the BBB.