Expression of the immediate early response gene c-fos is induced by several cellular and extracellular stress factors including ionizing radiation. We examined the role of c-fos in mediating stress-induced apoptosis of isogenic CD4+ and CD8+ mouse T-lymphocytes differing only in their c-fos status after treatment with ionizing radiation and the synthetic glucocorticoid dexamethasone. The amount of radiation-induced apoptosis was decreased (up to 37%) in the T-lymphocyte population derived from the knockout mice lacking endogenous c-fos compared to the wildtype T-lymphocyte population. The difference in apoptosis induction in T-lymphocytes from wildtype and c-fos knockout mice was even more prominent (up to 55%) after dexamethasone treatment. Comparative experiments were performed with T-lymphocytes from isogenic mouse littermates differing only in the status of the tumor-suppressor gene p53. Whereas p53 plays a primary role in radiation-induced apoptosis, our results suggest that c-fos enhances both p53-dependent radiation- and p53-independent steroid-induced apoptosis in T-lymphocytes.