AbstractMany tumors express the death ligand CD95L (CD178, APO‐1L, FasL) and can kill activated T cells in vitro. This may enable the tumor cells to suppress anti‐tumor immune responses, a phenomenon called "tumor counterattack". Preliminary evidence of tumor counterattack in human tumors exists. However, CD95L‐expressing tumors are rapidly rejected in mice. In order to clarify this controversial situation we investigated whether the level or the time point of CD95L expression might be critical factors determining tumor counterattack versus tumor rejection. We generated CD95‐resistant tumor cell lines expressing different levels of CD95L (LKC‐CD95L). In nude mice the CD95L expression level had no influence on the growth of the CD95L+ tumors. In contrast, a CD95L– control tumor cell line (LKC) grew much faster. In addition, we generated a CD95‐resistant cell line in which CD95L was induced via the tet system (LKCR‐tetCD95L). Induction of CD95Lin established tumors in nude and NOD/SCID mice led to rapid rejection of the tumors. Induction of lower CD95L expression levels delayed tumor rejection only marginally. These results demonstrate that rejection of CD95L‐expressing tumors in mice is not a result of overexpression and does not depend on the presence of CD95L at the onset of tumor progression.