Virulent strains of Staphylococcus hyicus can cause exudative epidermitis in pigs. The major symptom of this disease is exfoliation of the skin in the upper stratum spinosum. Exfoliation of the skin is strongly associated with exfoliative toxin including ExhA, ExhB, ExhC, ExhD, SHETA, and SHETB. Recently, genes for ExhA, ExhB, ExhC and ExhD were cloned. Exfoliative toxins produced by S. aureus have been shown to selectively cleave human or mouse desmoglein 1, a desmosomal adhesion molecule, that when inactivated results in blisters. In this study, we attempted to identify the molecular target of Exhs in porcine skin. Each of recombinant Exhs injected in the skin of pigs caused superficial epidermal blisters or crust formation. Cell surface staining of desmoglein 1, but not that of desmoglein 3, was abolished when cryosections of normal porcine skin were incubated with one of Exhs suggesting that Exh selectively degrade porcine desmoglein 1. In vitro incubation of the recombinant extracellular domains of desmoglein 1 and desmoglein 3 of human, mouse or canine origin demonstrated that only mouse desmogleins 1alpha and 1beta were cleaved by ExhA and ExhC at high concentration. Furthermore, injection of ExhA and ExhC at high concentration caused superficial blisters in neonatal mice. These findings strongly suggest that Exhs cause blister formation of porcine skin by digesting porcine desmoglein 1 in a similar fashion to exfoliative toxins from S. aureus.