The presence of T lymphocytes bearing the gamma-delta-T-cell receptor (TCR-gamma-delta) has been studied immunocytochemically in central nervous system (CNS) tissue from 13 patients with multiple sclerosis (MS), 4 with inflammatory non-MS CNS disorders, 6 with other neurological diseases, and 3 with nonneurologic conditions. Twenty-eight of 43 MS lesions contained TCR-gamma-delta-cells and these were most frequently found in chronically demyelinated areas, in contrast to the previously studied CD4+, CD8+ (TCR-alpha-beta) population, which predominated in more active lesions. Some TCR-gamma-delta-lymphocytes had an unusual morphology with long dendritic processes, which were sometimes interconnected forming a network. Because it is generally believed that TCR-gamma-delta-lymphocytes function in a cytotoxic fashion in association with heat shock proteins (hsp), we examined the colocalization of TCR-gamma-delta-cells with 65- and 70-kDa hsp (hsp65 and hsp70) in MS lesions. Hsp65 was expressed on immature oligodendrocytes at the margins of chronic lesions containing TCR-gamma-delta-lymphocytes. The coexpression of these molecules might imply functional relationships perhaps of significance to the chronicity of the MS disease process and the failure of CNS remyelination.