We investigated the effect of Fas/APO1-ligand (CD95L) gene transfer on allogeneic immune responses in vivo. A colon carcinoma cell line from BALB/c mice, CT26, was stably transfected with a vector encoding mouse CD95L and was inoculated into C57BL/6 mice. CD95L expression markedly reduced allogeneic cytotoxic T lymphocyte and helper T lymphocyte activity directed toward CT26. Strikingly, expression of CD95L on these allogeneic tumors completely inhibited the generation of alloantibodies of both IgM and IgG subclasses. Thus, CD95L inhibited alloantibody production and conferred localized immune suppression through this mechanism. These results provide insight into the role of CD95L in regulating the alloantibody response and the generation of local immune responses.