The alpha beta T-cell antigen receptor (TCR) recognizes antigenic peptides in the context of self major histocompatibility complex (MHC) molecules. The specificity of recognition of MHC plus antigen is generally determined by a combination of the variable elements of alpha- and beta-chains of the TCR. Several types of antigen, however, have been identified that, when bound to MHC molecules, stimulate T cells bearing particular variable-region beta-chain (V beta) elements irrespective of the other variable components of the TCR. These have been termed 'superantigens', and here we are concerned with one type of superantigen, the toxins produced by Staphylococcus aureus. T cells have been found that bear closely related members of the same V beta family but respond differently to S. aureus toxins; in particular, cells bearing the human V beta 13.2 element respond to toxin SEC2, whereas cells bearing human V beta 13.1 do not. We have now defined the residues of the V beta element responsible for this difference, and find that they reside in a region thought to lie on the side of the TCR molecule, away from the conventional antigen/MHC-binding site. The evolutionary conservation of this site may be due to its having an important role in some function of the TCR other than the binding of conventional antigen plus MHC.