It is well documented that donor bone marrow in combination with peri-transplant anti-thymocyte globulin (ATG) administration induces transplantation tolerance in a variety of animal models. Our previous work showed that the ability of donor marrow to induce tolerance was dependent on the presence of CD95 ligand (Fas-ligand) on the donor cells. In this study we investigate whether CD95 (Fas) on the recipient cells is required. By comparing skin allograft survival times between wild-type C57BL/6 ATG-treated recipients and C57BL/6lpr/lpr ATG-treated recipients (which do not have a functional CD95 gene), we show that donor bone marrow could induce indefinite transplant survival (median survival time >200 days) only in recipients with a functional CD95 gene. Thus, we conclude that the CD95 ligand-CD95 apoptotic pathway plays a major role in donor bone marrow-induced transplantation tolerance.