It has been hypothesized that the progressive deletion of CD4+ T cells in the course of infection due to human immunodeficiency virus (HIV) may be mediated in part by interaction with a superantigen inherent in an HIV protein. Consequently, selective loss of CD4+ cells with a T cell receptor Vβ-chain capable of interaction with superantigen would produce a CD4 population less or totally unresponsive to superantigen such as staphylococcal enterotoxins B and A (SHU and SEA respectively), but not to other mitogens such as concanavalin A. anti-CD3 (OKT3). or pokeweed mitogen. We tested this hypothesis by comparing the proliferative response of SEB and SEA with the other mitogens for 25 controls. 20 HIV+. and 15 donors with acquired immune deficiency syndrome (AIDS). We found that peripheral blood mononuclear cells, as well as the CD4+ and CD8+ subsets from both HIV+ and AIDS sources, the degree of suppression of mitogenesis for SEB and SEA was approximately equal to or less than that of the other mitogens. Moreover. suppression of HIV+ CD4+ and CDS T cell responses to SEB and SEA was equal (26%). If HIV superantigens exist, our data suggest that they are not responsible for the selective depletion of the CD4+ T cell subset as evaluated by SEB and SEA specificity.