The extremely sensitive peritoneal exudate cell (PEC) transfer technique has been applied to an investigation of the immune response of female mice which are “tolerant” of the male antigen. Females rendered tolerant of male skin grafts by multiparity, neonatal inoculation of male spleen cells, or multiple inoculations of adult females with male lymphoid cells displayed second-set reactivity to male PEC while continuing to tolerate H-Y-incompatible skin grafts. Furthermore, this discordant response to male PEC and skin was adoptively transferrable to normal females by spleen cells from multiparous donors. Females rendered tolerant by irradiation and reconstitution with male cells were unresponsive to both H-Y-incompatible skin and PEC grafts. A model is proposed using two male-specific antigens, the response to which is controlled by independent genes.