CCAAT/enhancer-binding protein α (C/EBPα) is mutated in 10% of acute myeloid leukemias, resulting in either a truncated protein or an altered leucine zipper (C/EBPαLZ) that prevents DNA binding. C/EBPα induces bcl-2 in cooperation with nuclear factor-κB (NF-κB) p50 to inhibit apoptosis. We now demonstrate that C/EBPα or a C/EBPαLZ oncoprotein binds the bcl-2 P2 promoter in chromatin immunoprecipitation assays and induces the promoter dependent on the integrity of a κB site. C/EBPα expressed as a transgene in B cells binds and activates the bcl-2 promoter, but not in nfkb1−/− mice lacking NF-κB p50. Bcl-2 is central to the intrinsic apoptotic pathway, whereas FLICE inhibitory protein (FLIP) modulates caspase-8, the initiator caspase of the extrinsic pathway. C/EBPα and C/EBPαLZ also bind the FLIP promoter and induce its expression dependent upon NF-κB p50. Moreover, induction of FLIP by C/EBPα protects splenocytes from Fas ligand-induced apoptosis, but only if p50 is present. We also demonstrate the direct interaction between bacterially produced C/EBPα and NF-κB p50, mediated by the C/EBPα basic region. These findings indicate that C/EBPα or its oncoproteins activate the bcl-2 and FLIP genes by tethering to their promoters through bound NF-κB p50. Targeting their interaction may favor apoptosis of transformed cells.