LYMPHOCYTES are particularly susceptible to DNA damage-induced apoptosis, a response which may serve as a form of ’altruistic suicide’ to counter their intrinsic high potential for mutation and clonal expansion(1). The tumour suppressor p53 has been shown to regulate this type of apoptosis in thymocytes(2,3), but an as yet unknown, p53-independent pathway(s) appears to mediate the same event in mitogen-activated mature T lymphocytes(4). Here we show that DNA damage-induced apoptosis in these T lymphocytes is dependent on the antioncogenic transcription factor interferon regulatory factor (IRF)-1 (refs 5-7). Thus two different anti-oncogenic transcription factors, p53 and IRF-1, are required for distinct apoptotic pathways in T lymphocytes. We also show that mitogen induction of the interleukin-1 beta converting enzyme (ICE) gene(8-10), a mammalian homologue of the Caenorhabditis elegans cell death gene ced-3, is IRF-1-dependent. Ectopic overexpression of IRE-1 results in the activation of the endogenous gene for ICE and enhances the sensitivity of cells to radiation-induced apoptosis.