Lymphocyte infiltration and microglial activation in experimental autoimmune encephalomyelitis (EAE) are mainly centred on the spinal cord. However, a cryolesion to one cerebral hemisphere (cryolesion-EAE) induces six-fold enhancement of EAE in the cerebral hemispheres and removal of the cervical lymph nodes reduces such enhancement by 40 per cent. This study tests the hypothesis that lymphocytes from donor rats with cryolesion-EAE will selectively target the brain rather than the spinal cord when transferred to naive recipients. Acute EAE was induced in 15 Lewis rats (donors); ten donors received a cryolesion to the left cerebral hemisphere 8 days post-inoculation of antigen and adjuvant. Five rats with EAE received no cryolesion. Lymphocytes from cryolesion-EAE donors or from EAE-only donors were cultured for 72 h in medium containing myelin basic protein and then injected into a total of 21 naive recipients, which were killed 8 days later. The severity of EAE in brains and spinal cords was assessed in immunocytochemically stained sections by quantifying the number of vessels showing lymphocyte cuffs (W3/13 antibody) and the level of MHC class II antigen expression by microglia (OX6 antibody). When compared with recipients of EAE-only donor lymphocytes, the severity of cerebral EAE was increased 2- to 2.6-fold in the recipients of crylesion-EAE donor lymphocytes (p < 0.01); EAE in the spinal cord was reduced. These results suggest that lymphocytes from cryolesion-EAE donors preferentially target the brain in recipient animals in preference to the spinal cord. By analogy with cryolesion-EAE, focal central nervous system (CNS) damage with drainage of auto-antigens to regional lymph nodes in man may play a role in determining the site and timing of initial and recurrent multiple sclerosis lesions.