Serious staphylococcal infections frequently begin in the skin. The present study used a mouse model of such infections to evaluate the ability of Staphylococcus aureus to disseminate from the skin and to determine if cutaneous damage from the infections was required for dissemination. The mice were inoculated with S. aureus onto flank skin prepared by a tape-stripping method that caused minimal disruption of the epidermal keratinocyte layers. After these inoculations the staphylococci were found to disseminate to the spleen and kidneys of almost all animals within 6h. Induction of leucopenia did not affect this process. Cutaneous damage was prominent in these experimental infections and included loss of the epidermis, neutrophil infiltration into the epidermis, and complete necrosis of the dermis. The latter also occurred in cyclophosphamide-treated animals, indicating that the organisms themselves and not the host inflammatory responses were responsible. Dermal necrosis did not develop until 48h after inoculation, a time by which dissemination had already occurred. Therefore, in this mouse model system S. aureus is capable of penetrating the epidermal keratinocyte layers and disseminating rapidly after inoculation; the experimental infections do produce significant dermal damage, but the latter develops after dissemination has already taken place.