Activation of resting T cells usually leads to their proliferation and differentiation into effector cells and a subsequent decline following elimination of the antigen. A situation of excessive antigen density may result in T cell receptor (TCR)‐induced deletion of T effector cells, a process termed antigen‐induced cell death (AgICD). Previous studies indicate that AgICD of cytotoxic T cells may be induced by either of the two key cytotoxic processes, granule exocytosis, including perforin and granzymes, or the Fas ligand (FasL)/Fas pathway. By using in vitro‐polyclonallyactivated or ex vivo‐derived virus‐induced T cell populations from mice with mutations or targeted gene defects in one or more components of the two key cytolytic pathways we now show thatTCR‐induced apoptosis is only impaired in the absence of FasL and/or Fas, but not in the absence of perforin and/or granzymes. Furthermore, antibody‐blockage of FasL alone is sufficient to inhibit early T cell death. Inhibition of both, FasL and tumor necrosis factor (TNF‐α) is required to abrogate late apoptosis by AgICD. The fact that antibodies to IFN‐γ also inhibit AgICD suggests that theperforin plus granzyme‐independent and FaSL and/or TNF‐α facilitated process of AgICD of T effector cells is tightly regulated by endogenous IFN‐γ.