Recognition of superantigens by T cells predominantly involves the TCR V beta region. The contribution of reactivity from the non-V beta portion of the TCR remains less clear. We have investigated the V alpha repertoire of T cells bearing one V beta element responding to different superantigen or polyclonal stimuli. The data indicate that the V alpha chain is not directly involved in superantigen recognition, since unrelated superantigens do not stimulate cells bearing different V alpha elements. Instead, analysis of V alpha elements used preferentially in the CD4+ or CD8+ cells, shows that the V alpha-regions predominating in the superantigen response are the same V alphas that are positively selected into the CD4+ lineage. Thus the ability of a V alpha-region to either aid or hinder the interaction with class II predicts its frequency in a superantigen-responding population of T cells.