The identification of activated T cells in the brain of individuals with multiple sclerosis (MS) indicates that these cells are critical in the pathogenesis of this disease. In an attempt to elucidate the nature of the lymphocytic infiltration, we used the polymerase chain reaction to amplify T-cell antigen receptor (TCR) V alpha sequences from transcripts derived from MS brain lesions. In each of three MS brains, only two to four rearranged TCR V alpha transcripts were detected. No V alpha transcripts could be found in control brains. Sequence analysis of transcripts encoded by the V alpha 12.1 region showed rearrangements to a limited number of J alpha region segments. These results imply that TCR V alpha gene expression in MS brain lesions is restricted.