Interleukin-1 alpha (IL-1 alpha), an immunoregulatory protein secreted by the peripheral immune system, affects the central nervous system (CNS). IL-1 alpha could directly enter the parenchyma of the brain in intact form to alter brain function, or it could be blocked or sequestered by the capillary bed comprising the blood-brain barrier (BBB) that normally retards entry of circulating proteins to the brain and cerebrospinal fluid (CSF). We show here by use of the selective interleukin receptor antagonist (IL-1ra), capillary depletion method, high performance liquid chromatography (HPLC) and saturation with unlabeled IL-1 alpha that radioactively labeled IL-1 alpha injected iv directly enters the CNS in intact form. This also occurs in the brain cortex, an area devoid of circumventricular organs (CVOs), and in the CSF, an area devoid of capillaries. Capillaries can also sequester IL-1 alpha in a saturable manner, suggesting that they may be the site for the carrier-mediated entry of IL-1 alpha into the CNS. Thus, the results show that circulating IL-1 alpha has direct access to cortical brain cells behind the BBB through a saturable transport system that provides a major pathway by which the brain and immune system interact.