Seventeen T-cell clones derived from the peripheral blood of a patient with multiple sclerosis and reactive with a synthetic peptide corresponding to residues 152-170 of the human myelin basic protein molecule were previously shown to be cytotoxic for myelin basic protein-coated target cells. Genetic restriction studies have now demonstrated that these clones recognize myelin basic protein in association with human leukocyte antigen DRw13. Studies of the T-cell receptor beta gene rearrangements generated by these clones demonstrated 12 different patterns, as evaluated by Southern blot analysis. Thus, the human T-cell response to myelin basic protein is exceedingly heterogeneous, even among T cells that recognize the same small fragment of the molecule in association with the same class II restriction element.