Deletion of mature T cells maintains cellular homeostasis and is involved in the maintenance of self tolerance to some peripheral self antigens. Previous studies have presented conflicting evidence for a role of the tumor necrosis factor receptor (TNFR) family member CD95 (Fas) in peripheral T cell deletion using CD95-deficient mice. To evaluate cooperation between CD95 and another TNFR family molecule, TNFR1, we generated mice deficient for both CD95 and TNFR1. We showed that TNFR1 and CD95 do not contribute to the decline of antigen-specific cytotoxic T lymphocytes after virus infection. Using TNFR1 / CD95-deficient mice expressing the P14 TCR specific for a lymphocytic choriomeningitis virus-derived peptide (p33) we showed that deletion of p33-specific CD8(+) T cells following high dose p33 administration is also normal. However, in non-TCR-transgenic TNFR1 / CD95-deficient mice treated with the same p33 regimen, tolerance induction was defective. These data indicate that TNFR1 and CD95 are dispensable for deletion of antigen-specific T cells after viral infection. However, under certain conditions, both TNFR1 and CD95 appear to cooperate in CD8(+) T cell deletion.