Minor histocompatibility (H) antigens create a barrier to the transplantation of organs and tissues between individuals matched for strong antigens, encoded by the major histocompatibility complex (MHC) in humans and by H-2 in mice. The male-specific antigen H-Y, which belongs to H antigens, provides a well-characterized system for studying graft rejection. C57BL/6 female mice are able to generate a strong cellular response against syngeneic male grafts. This reaction can be alleviated by immunosuppressive drugs, but they are usually hepatotoxic and increase the risk of infection and tumor development. Our previous works showed that epicutaneous (ec) immunization with protein antigen led to a profound antigen-non-specific suppression of some aspects of cell-mediated immunity (e.g. contact hypersensitivity, delayed-type hypersensitivity). The present study was aimed at checking the effect of ec pretreatment of female C57BL/6 mice with ovoalbumin (OVA) on the survival of syngenic male skin transplants. Indeed, we found that ec immunization with a protein antigen prior to grafting significantly prolonged the survival of the graft. The ease of application makes ec tolerization an attractive treatment strategy for the suppression of graft rejection.