Interferons (IFNs) are cytokines that produce effects in the CNS even though their production occurs mainly in the periphery. Direct passage of IFNs from blood to CNS could be an important route by which circulating IFNs exert their central effects. In this report, we characterize the pharmacokinetics of the passage of IFNs through the blood-brain and blood-spinal cord barriers in four separate regions: whole brain and the cervical, thoracic and lumbosacral segments of the spinal cord. We found that the spinal cord had greater permeability to IFNs than did the brain. For each corresponding region, the permeability to IFN alpha was higher than that to IFN gamma. Capillary depletion after cardiac perfusion showed that most of the injected IFN was not entrapped by the vasculature but entered the parenchyma of the brain. HPLC showed that most of the IFN gamma entered in intact form. The passage of radioactively labeled IFN gamma into the brain and cervical spinal cord was saturated by a low dose of unlabeled IFN gamma, while passage into the thoracic and lumbosacral spinal cord was not saturated. In contrast, for another cytokine, tumor necrosis factor alpha (TNF alpha), a saturable transport system was present in distal spinal cord as well as the brain. The results show that IFNs and TNF alpha can enter the CNS from the periphery but with regional differences.