Aberrant expression of TAL1 occurs frequently in human T-cell acute lymphoblastic leukemia. The effect of TAL1 expression in the T-cell lymphoid precursor, however, remains unclear. In the current study, we have developed TAL1 stable transfectants in a human immature T-cell lymphoid cell line. Whereas no effect on proliferation, cell culture density, or cell cycle was detected, the transfectants were more resistant than the parental cell line to apoptosis induced by chemotherapeutic agents including etoposide, daunorubicin, doxorubicin, cytosine arabinoside, methotrexate and vincristine and also to apoptosis induced by Fas/CD95 cross-linking. This effect was independent of the cytostatic effects of the drugs. The basic domain-deleted transfectants did not demonstrate altered sensitivity, suggesting that DNA binding was necessary for resistance to apoptosis. The ability to alter the response to a wide range of cell death-inducing stimuli suggests that TAL1 acts at a late stage of the apoptotic cascade. These data therefore provide direct evidence of an antiapoptotic effect of ectopic TAL1 expression in response to cytotoxic agents, thus providing insight into its oncogenic function in T-cell acute lymphoblastic leukemia and a novel experimental model to further investigate the underlying mechanisms. These data also have potential practical significance for cytotoxic therapy of this disorder.