Despite the evidence for immunological reactions in the human CNS, in viral encephalitis and in multiple sclerosis, connections between the brain and the immune system are poorly understood. In rodents, tracers injected into the interstitial fluid of the brain drain to the cervical lymph nodes by perivascular pathways in the brain and nasal lymphatics. Similar pathways could serve as lymphatics in the human brain. In the present study, we test the hypothesis that lymphatic drainage of the brain and cervical lymph nodes play a key role in T-cell mediated immunity of the brain. Experimental allergic encephalomyelitis (EAE) was induced in Lewis rats by the injection of guinea pig spinal cord homogenate in complete Freund's adjuvant into the foot pads. This resulted in paralysis of the hind limbs and infiltration of lymphocytes and microglial activation centred mainly on the spinal cord; little inflammation was seen in the cerebrum. When a brain wound, in the form of cryolesion, was inflicted on one cerebral hemisphere, 8 days after the induction of EAE, there was a 6-fold enhancement of EAE lesions in the brain. This enhancement was reduced by 40% cervical lymphadenectomy at the time of the cryolesion. These results suggest that cervical lymph nodes play a pivotal role in cerebral EAE and may be a major source of brain-directed lymphocytes. If similar mechanisms apply in man, study of cervical lymphocytes and their manipulation could open new therapeutic avenues for the treatment of multiple sclerosis.