Circulating interleukin-1 alpha (IL-1 alpha) has multiple effects on the central nervous system. We investigated the ability of radioiodinated IL-1 alpha (rIL-1 alpha) to cross the rodent blood-brain barrier and found its entry rate to be 43.9 times greater than that predicted by leakage alone. The rIL-1 alpha entered multiple regions of the brain, with over 40% entering at the cortex. The hypothalamus had the highest entry rate on a weight basis but only accounted for 2% of total entry. In all experiments, the entry rate of rIL-1 alpha greatly exceeded that of simultaneously injected radiolabeled albumin. The half-time disappearance of rIL-1 alpha from the brain after central injection was 21.9 min, a time that exceeds the reabsorption rate of cerebrospinal fluid. Pretreatment of animals with aluminum decreased both entry and exit rates, which is compatible with a saturable component of transport. Thus, rIL-1 alpha has access to many regions of the brain with bidirectional transport rates across the blood-brain barrier exceeding those predicted by nonspecific mechanisms.