Age-related thymic involution, which is linked to senescence of the immune system, was found to be mediated by the death receptor Fas. The thymus of aged Fas(-/-) mice exhibited an intact structure and the normal differentiation of thymocytes. Both thymocytes and thymic epithelial cells (TECs) were sensitive to Fas-mediated apoptosis, and in vivo stimulation of wild-type thymocytes with anti-CD3 mAb was shown to induce apoptosis in TECs in a Fas-dependent manner. In addition, thymopoiesis continued uninterrupted in aged Fas(-/-) mice that had been lethally irradiated and reconstituted with bone marrow cells derived from wild-type mice, while age-related thymic involution was observed in irradiated wild-type mice reconstituted with bone marrow cells from either Fas(-/-) or wild-type mice. The results indicate that Fas on TECs plays a key role in age-related thymic involution.