Macrophage inflammatory proteins (MIP)-1 alpha and -1 beta have been postulated to exert their pyrogenic effects by acting directly at sites within the brain. Such activity would require circulating MIP-1s to cross the blood-brain barrier (BBB). We examined the ability of the monomer and polymer of MIP-1 alpha and the polymer of MIP-1 beta radioactively labeled with 125iodine (I-MIP-1) to cross the BBB. These I-MIP-1s behaved very similarly to each other but in a manner not previously seen for other cytokines. The I-MIP-1s immediately associated to a high degree and in a reversible manner with the vascular space of the brain. This association did not increase over time nor was it self-inhibitable. These results make it unlikely that the MIP-1s are transported into the brain by saturable transport systems in the manner found for some of the other cytokines. Other mechanisms, such as interactions with brain endothelia, leakage into brain through extracellular pathways, and binding at circumventricular organs, are more likely to provide the mechanisms through which blood-borne MIP-1s affect the central nervous system.