A skin lesion was induced by the subcutaneous injection of herpes simplex virus in mice. The incidence of lesions was dose-dependent, but the size of the lesions, once formed, was independent of the initiating dose. The incidence of lesions was also independent of age in mice between 5 weeks and 5 months old, but the number of mice dying after forming lesions decreased with the increasing age of the mice. Viral dissemination from the lesion into the blood and central nervous system was observed 5 to 6 days following injection in 5-week-old mice. The growth curve of the virus during the first 27 hours after injection could be related to those obtained in tissue culture studies. The amount of virus in the lesion during the first 10 days after injection increased to a peak of per g of skin by the 5th day and then diminished to per g of skin by the 10th day. The local progression of the virus within the lesion was demonstrated with the use of fluorescent antibody staining methods. Specif- ic fluorescence was localized only in cells of epidermal origin after the 2nd day, and the histopathology of the lesion showed degeneration of epidermal cells. The similarities between this mouse lesion and human herpes simplex dermatitis suggest that it may serve as a model of this infection in man.