Urtica dioica agglutinin (UDA) is a superantigen that, in vitro, binds to specific carbohydrate structures on class II and induces a sixfold enrichment of V beta 8.3+ BALB/c mice splenic T cells. Superantigens have pleiotropic effects in vivo, causing the activation, proliferation, and deletion of specific T cells, but are heterogenous in regard to their effects on T cell tolerization. We, therefore, compared the responses of peripheral T cells from adult BALB/c mice with the i.v. injection of 50 micrograms UDA or the bacterial superantigen staphylococcal enterotoxin B (SEB) that also recognizes the V beta 8.3 gene product. The data presented indicate that activation, clonal expansion, anergy, and death of V beta 8.3+ T cells occur sequentially after UDA administration. Two days after UDA injection, the proportion of V beta 8.3+ T cells in the periphery is elevated to approximately twice that of normal mice. This expansion occurs in both CD4+ and CD8+ subsets. V beta 8.3+ T cells from UDA-primed mice are anergic to UDA restimulation and fail to proliferate or to produce IL-2. Futhermore, the proliferation of V beta 8.3+ T cells is followed by their rapid disappearance concomitant with their specific elimination by apoptosis. In 1 wk, all CD4+ V beta 8.3+ peripheral T cells are deleted. The decline of V beta 8.3+ T cells in the CD4+ subset is more than in the CD8+ subset. This occurs in thymectomized and in thymus-intact animals. Two months after UDA priming, the percentage of V beta 8.3+ T cells is still lower than in control mice.