Chronic relapsing experimental allergic encephalomyelitis was induced by the passive transfer of [14C]thymidine-labeled myelin basic protein (MBP)-sensitized lymphocytes from MBP-immunized mice to naive syngeneic recipients. Labeled lymphocytes were localized and quantitated in the central nervous system during acute and chronic disease and clinical relapses. The results have shown that MBP-immune T cells home to the central nervous system endothelium 24 hours prior to and during initial clinical disease (5 to 7 days posttransfer). Unexpectedly, labeled MBP-immune cells never migrated far from blood vessels and, despite the presence of massive parenchymal inflammatory cell infiltration, almost invariably remained within the perivascular area. Quantitation revealed that labeled cells represented a minority (usually 1% to 4%) of the inflammatory cells during acute and early chronic disease. Furthermore, labeled cells could not be demonstrated in the central nervous system at the time of clinical relapse. We conclude that in this model, MBP-immune lymphocytes act exclusively from a perivascular location to orchestrate the influx of inflammatory cells that are predominantly of recipient derivation.