The ETS family transcriptional repressor TEL is frequently disrupted by chromosomal translocations, including the t(12;21) in which the second allele of TEL is deleted in up to 90% of the cases. Consistent with its role as a putative tumor suppressor, TEL expression inhibits colony formation by Ras-transformed NIH 3T3 cells and hinders proliferation of a variety of cell types. Although we observed no alteration in the cell cycle of TEL-expressing cells, we did find a marked increase in apoptosis of serum-starved TEL-expressing NIH 3T3 cells. This decrease in cell survival required the DNA binding domain of TEL, suggesting that TEL repressed an anti-apoptotic gene. These observations prompted us to search for genes regulated by ETS family proteins that regulate apoptosis. The anti-apoptotic molecule Bcl-XL contains multiple ets-factor binding sites within its promoters, and TEL repressed a Bcl-XL promoter-linked reporter gene. Moreover, the enforced expression of TEL decreased the endogenous expression of both Bcl-XL mRNA and protein. TEL-mediated repression of Bcl-X L likely affects cell survival via regulation of the apoptotic pathway.