Contagious ecthyma and goat pox viruses were isolated from goats affected with papulopustular epidermal lesions. Results of in vitro serum neutralization and in vivo cross-immunity studies indicate that these contagious ecthyma and goat pox isolates from the western United States are antigenically dissimilar and that exposure or vaccination with one isolate could not be used as a method of inducing immunity to the other. Exposure to each isolate conferred immunity to re-exposure with the same agent. The serum neutralization test indicates that the severity and persistance of lesions to goat pox infection influences the nature of the antibody response to an initial exposure.