Interaction of staphylococcal exotoxins (SE) with MHC class II molecules plays a central role in the activation of immune cells by SE. We have recently demonstrated directly that toxic shock syndrome toxin-1 (TSST-1) binds to MHC class II molecules with high affinity, and similar results have been reported for SEA and SEB. The ability of T cells to respond to individual SE is associated with the expression of particular TCR-V beta gene elements. In the present study we have examined the effect of polymorphism on the ability of MHC class II molecules to bind SEB and TSST-1. We have used a panel of L cell transfectants that express different allelic forms of each of the three human class II isotypes. Radioligand binding assays detected binding of SEB and TSST-1 to most, but not all of the MHC class II molecules examined. Toxin-driven MHC class II-dependent T cell proliferation occurred with all transfectants examined even in the absence of detectable toxin binding. These results indicate that SE can bind to human MHC class II molecules of diverse phenotypes.