Sera from normal humans were cytotoxic to autologous and allogeneic epidermal cells. Sera from newborns were not cytotoxic, which is consistent with earlier results suggesting the gradual development of autoantibodies in animals. With anti-human IgG fluorescein-labeled conjugate staining, it was shown that the outer layers of the epidermis were stained by the natural autoantibody. No staining, however, was noted with sera from newborn cord blood. Another autoantibody induced by burns associated with autograft rejection was found to stain specifically the cells of the basal layer of the epidermis. The basal layer cells were not stained by HL-A antibodies. It is concluded that autoantibodies to the outer layers of the human epidermis occur naturally, and autoantibodies to the basal layer can be induced by burn injury associated with autograft rejection.