Notch signaling has been established as a key regulator of cell fate in development, differentiation, and homeostasis. In breast cancers, increased Notch1 and Notch4 activity have been implicated in tumor progression and, accumulation of the intracellular domain of Notch4 (ICN4), reported in basal breast cancer cells. While, TNF-related apoptosis-inducing ligand (TRAIL) receptor agonists have demonstrated selectively in targeting tumor cells, the majority of primary tumors are resistant to TRAIL. This necessitates the identification of factors that might regulate TRAIL sensitivity. Here we investigate TRAIL sensitivity in tumor cells following the modulation of Notch (1 and 4) activity using siRNA-mediated depletions or ectopic expression of GFP-tagged constructs of the intracellular domains of Notch1 (ICN1) or Notch4 (ICN4). Our findings suggest that Notch4, but not Notch1 signaling, sensitizes breast tumor cells to TRAIL-induced apoptosis. ICN4-induced sensitization to TRAIL is characterized by CBF1-dependence. Apoptosis was mediated via caspase-8 activation and regulated by the Bcl-2 family pro-apoptotic proteins Bak and Bid. Finally, we present evidence that endogenous Notch4 activity regulates susceptibility to TRAIL in basal-like breast cancer cells but not in cell lines of luminal origin. These experiments reveal a hitherto unexplored Notch4-TRAIL signaling axis in breast cancer cells.