Multiple sclerosis (MS) has a wide spectrum of clinical courses, character ized by multifocal central nervous system (C NS) damage, postulated to be mediated by C NS antigen-specific T cells. Dendritic cells (DC), the most potent antigen-presenting cell, play a pivotal role in the decision between T-cell activation or anergy. Monoclonal antibodies to C D1a (immature DC) and C D83 (mature DC) were used to screen lesions with evidence of recent demyelinating activity and chronic plaque and normal appearing white matter (NAWM) tissue sections from 12 MS cases by immunocytochemistry. No C D1a-positive cells were detected in the MS or control C NS tissue blocks investigated. C D83-po sitive cells were not detected in tissues from any of the control cases or in the majority of perivascular cuffs in the MS tissue sections. However, in eight of the MS tissue blocks with evidence of recent demyelination, and in one block each from chronic plaque and NAWM, small numbers of distinct C D83-positive cells were present within occasional perivascular cuffs. In one area only of MS NAWM were C D83-po sitive cells detected in the tissue parenchyma, in an area of intense immunological activity. DC in MS tissue may originate in the peripheral circulation as monocytes or immature DC and migrate to areas of plaque in response to signals received from C NS-produced chemokines.