Although anatomical barriers and soluble mediators have been implicated in immune privilege, it appears that the apoptotic cell death of Fas+ cells by tissue-associated CD95 ligand (Fas ligand, FasL) is an important component. One clinical example of the function of an immune privileged site is the success of human corneal transplants, where a very high percentage of transplants accept without tissue matching or immunosuppressive therapy. Since the mouse cornea expresses abundant Fas ligand and immune privilege has been implicated in the success of these transplants, we examined the role of FasL in corneal transplantation. Our results show that human corneas express functional FasL capable of killing Fas+ lymphoid cells in an in vitro culture system. Using a mouse model for corneal allograft transplantation, FasL+ orthografts were accepted at a rate of 45%, whereas FasL- grafts, or normal grafts transplanted to Fas- mice, were rejected 100% of the time. Histological analysis found that FasL+ grafts contained apoptotic mononuclear cells indicating the induction of apoptosis by the graft, while rejecting FasL- corneas contained numerous inflammatory cells without associated apoptosis. Taken together our results demonstrate that FasL expression on the cornea is a major factor in corneal allograft survival and, thus, we provide an explanation for one of the most successful tissue transplants performed in humans.