Summary Staphylococcus aureus enterotoxin H (SEH) belongs to the staphylococcal enterotoxin (SE) family of superantigens (SAgs). SEH has structural similarities to other SE; however, its biological properties are less well characterized. SEH binds with high affinity to human major histocompatibility complex (MHC) class II and exhibits strong mitogenic activity in human T cells, although it was found to be less potent than the related SEA. Surprisingly and in sharp contrast to related SEs, SEH did not possess superantigen activity in murine T cells and T cells from three investigated rat strains. However, SEH bound to a high extent to murine MHC class II expressing cells and when presented by these cells SEH stimulated human T cells to proliferate. Thus, SEH interacts with the murine MHC class II molecule in a functional manner. Notably, SEH had an inhibitory effect on murine SEA response, demonstrating that SEH interferes with the SEA interactions with murine cells. Despite this, murine T cells did not proliferate regardless of whether SEH was presented on human or murine MHC class II expressing cells. Consequently, SEH differs in species reactivity as compared to related SEs and lacks critical properties for T‐cell activation in mice. We propose that unlike other SEs, SEH does not interact with murine T cells since it is not recognized by murine T‐cell receptors.