It has been proposed that toxins and other bacterial protein products of Staphylococcus aureus can act as triggers or persistence factors in several inflammatory skin diseases. In this study, we examined the S. aureus isolates from the skin of patients with atopic dermatitis and psoriasis. We found that the bacterial isolates from these patients exihibited either characteristics superantigenic toxins or thermolabile toxins believed to be staphylococal α-toxin. All of these staphylococcal strains also secreted extracellular staphylococcal protein A. We found significant differences in the action of these toxins on human keratinocytes and keratinocyte cell lines. The superantigenic toxins toxic shock syndrome toxin–1, staphylococcal enterotoxins A and B, and exfoliative toxin–A. as well as staphylococcal protein A, did not induce significant cytotoxic damage in the keratinocyte cell line HaCaT, whereas the staphylococcal α-toxin produced profound cytotoxicity. Keratinocyte cytotoxity induced by staphylococcal α-toxin was time and concentration dependent and demonstrated the morphologic and functional characteristics of necrosis, not apoptosis. Addition of α-toxin to keratinocytes simultaneously induced cell lysis and tumor necrosis factor–α release into the medium within 30 min; apparently, it was constitutive tumor necrosis factor–α. On the other hand, superantigenic toxins and, in particular, protein A showed stimulation of tumor necrosis factor-α secretion in keratinocytes and release of this cytokine after 6–12 h of incubation. Thus, staphylococcal protein A, α-toxin, and superantigenic toxins found in S. aureus isolates from patients with psoriasis and atopic dermatitis can produce direct pro-inflammatory effects on kerationcytes through the release of tumor necrosis factor–α. We propose that these effects may be relevant to the induction and persistence of lesions in these two diseases