Recent work has shown that interleukin-1 alpha (IL-1 alpha) and IL-1 beta are transported from blood to brain across the blood-brain barrier by a saturable system. Here, we show that the endogenous IL-1 receptor antagonist (IL-1ra) radioactively labeled with either 125I or 35S is also transported across the blood-brain barrier by a saturable transport system. Between 0.33 and 0.65% of an intravenous dose of labeled IL-1ra entered each gram of brain. The three cytokines inhibited each other's transport in a way suggesting that their elevated blood levels would tend to favor the entry of IL-1 beta at the expense of IL-1 alpha. High performance liquid chromatography confirmed that radioactivity entering the brain represented intact cytokine. Recovery of radioactivity from cerebrospinal fluid, an area without blood vessels, and from the parenchymal fraction of the cortex, and area without circumventricular organs, after capillary depletion confirmed that blood-borne IL-1ra gained entry into the brain. The transport system for IL-1ra appeared to be linked to that for IL-1 alpha and IL-1 beta, but was not affected by IL-2, IL-6, TNF alpha, or MIP-1 alpha. The results show that IL-1ra circulating in the blood can cross the blood-brain barrier to enter the central nervous system.