The response of T lymphocytes to superantigens requires expression of the appropriate TCR V beta gene products as well as the establishment of cellular interactions mediated by adhesion molecules. To study the role of intercellular adhesion molecule (ICAM)-1 in the response in vivo to superantigens, we have analyzed the effects induced by the bacterial superantigen Staphylococcus aureus enterotoxin B (SEB) in mice which have been made genetically deficient in ICAM-1. SEB treatment of wild-type mice causes proliferation, deletion and anergy of the SEB-reactive V beta 8+ T cell population. Here we show that cellular interactions mediated by ICAM-1 are not essential for the induction of anergy or for the deletion of CD4+ V beta 8+ or CD8+ V beta 8+ T cells, but are required for the proliferation of these peripheral T lymphocytes. This is the first demonstration in vivo that the absence of the co-stimulatory signals provided by the interaction of ICAM-1 with its specific ligands impairs the proliferation of SEB-reactive T cells. Interestingly, our study showed that SEB-induced proliferation of CD8+ V beta 8+ T cells from lymph nodes (not from spleen) is independent of the interactions mediated by ICAM-1.