Extensive data indicate that the transcription factor NFκB is activated by signals downstream of oncoproteins such as Ras or breakpoint cluster region (BCR)ABL. Consistent with this, evidence has been presented that NFκB activity is required for Ras and BCR-ABL to transform cells. However, it remains unclear whether these oncoproteins activate a full spectrum of NFκB-dependent gene expression or whether they may augment or interfere with other stimuli that activate NFκB. The data presented here indicate that BCR-ABL expression in 32D myeloid cells or oncogenic Ras expression in murine fibroblasts blocks the ability of tumor necrosis factor (TNF) to activate NFκB. This suppression of NFκB is manifested by an inhibition of TNF-induced inhibitor of NFκB (IKK) activity and NFκB DNA binding potential but not by blocking TNF-induced nuclear accumulation of NFκB/p65. The inhibition of NFκB is not observed in oncogenic Raf-expressing cells and is not fully restored by the suppression of PI3-kinase or MEK pathways. Oncogenic Ras suppresses the ability of TNF to activate the expression of NFκB-dependent genes, such as iNOS (inducible nitric oxide synthase) and RANTES (regulated on activation normal T-cell expressed and secreted). These studies suggest that the ability of Ras and BCRABL to activate NFκB involves an uncharacterized pathway that does not involve classic IKK activity and that suppresses the TNF-induced IKK pathway through a Raf/MEK/Erk-independent mechanism.