While superantigens such as staphylococcal enterotoxin B (SEB) have been shown to induce both clonal deletion and clonal anergy, it is still not known why tolerance rather than memory is induced. To address this issue, we tested the proliferative capacity of T cells from ovalbumin (OVA)-specific alpha beta T-cell receptor transgenic mice primed with either SEB emulsified in complete Freund's adjuvant (CFA) or with OVA peptide, the specific antigen, in CFA. By contrast cells from mice primed with SEB in CFA appeared to be anergic in that they were hyporesponsive to OVA peptide as well as to SEB. The anergic cells could respond to phorbol myristate acetate (PMA) and ionomycin, suggesting that a proximal signal transduction step was affected. Cells from transgenic mice primed with OVA peptide and CFA were not anergic and in fact displayed an enhanced response when they were challenged with OVA in vitro. Thus, when the two antigens are emulsified in CFA and then injected subcutaneously, they behave very differently: the superantigen SEB induces anergy whereas the conventional antigen OVA induces a memory type of response.