Staphylococcal enterotoxin B is known to be a powerful T cell stimulant in mouse and man. In this paper we show that, for mice, this is because the protein in association with major histocompatibility complex class II molecules stimulates virtually all T cells bearing VP3 and Vp6. 1, 8.2, and 8.3, and few others. Neonatal mice given the enterotoxin eliminate all mature, and some immature, T cells bearing these V (3s, demonstrating that tolerance to exogenously administered antigen can be caused by clonal deletion of reactive T cells. The enterotoxin shares these “superantigenic” properties with known self-antigens in mice, MIS-~= and Mls-2=, and a B cell-derived product, a shared property that is unlikely to be coincidental or inconsequential.