Multiple sclerosis is an autoimmune disease in which T lymphocytes reactive to myelin basic protein (BP) could play a central role. T cells specific for BP were cloned from the blood of multiple sclerosis patients and normal individuals, and expression of T-cell receptor variable region genes was analyzed. A remarkable bias for use of beta-chain variable region (V beta) 5.2 and, to a lesser extent, V beta 6.1 was seen among BP-specific clones from patients but not from controls. The preferential use of V beta 5.2 for BP recognition did not reflect altered expression of this V beta in the peripheral repertoire. Interestingly, shared V beta 5.2 usage was apparent for clones specific for different BP determinants, even when derived from the same individual. The concurrent demonstration by others (J. R. Oksenberg, M. A. Panzara, A. B. Begovich, H. Erlich, R. Murray, M. Sherritt, S. Stuart, C. C. Bernard, and L. Steinman, personal communication) that T cells within demyelinating areas of multiple sclerosis brains preferentially express V beta 5.2 and V beta 6.1 suggests that the BP-specific clones derived from blood may be relevant to disease pathogenesis. These findings may have important implications for the treatment of multiple sclerosis.