Interleukins (IL) are naturally occurring proteins that regulate, and thus link, both the immune system and the central nervous system (CNS). Since proteins are assumed not to be able to cross the blood-brain barrier (BBB), it is controversial how this linkage could occur. We show here that after iv injection of 125I-hIL-1 alpha, radioactivity in the brain eluted on HPLC in the position of the labeled cytokine. In addition, entry was inhibited by unlabeled hIL-1 alpha. Our demonstration of a saturable, carrier-mediated system that transports recombinant human IL-1 alpha in intact form from the blood into the CNS indicates a direct immune-CNS connection.