Mice were protected against the dermonecrotic effects of Staphylococcus aureus by previous infection with either coagulase-positive or coagulase-negative strains or by immunization with alpha-toxin. Passive protection was conferred by serum from previously infected mice or by alpha-antitoxin. While only some of these methods were associated with circulating alpha-antitoxin, in all cases there was a brisk early inflammatory response to infection. Furthermore, if the capacity of well immunized mice to mount such a response was removed, they were no longer protected against dermonecrosis. Conversely, non-immune mice developed little or no necrosis if the staphylococci were injected into areas of preexisting non-specific acute inflammation whether these had been produced chemically or immunologically. It is suggested that in this model of local infection with S. aureus an early inflammatory response, however provoked, is the major protective factor. Though specific neutralizing actions of antibodies are not excluded, the most important result of antibody-antigen reaction is to cause local inflammation by some form of immediate hyersensitivity.