Over-expression of the receptor tyrosine kinase erbB2 makes cancer cells resistant to apoptosis. α-Tocopheryl succinate (α-TOS), a redox-silent vitamin E (VE) analogue, has been shown to kill many different types of cancer cells. We tested whether α-TOS and several novel VE analogues kill breast cancer cells over-expressing the anti- apoptotic receptor protein erbB2 (HER2). Our experiments revealed that VE analogues caused comparable levels of apoptosis in breast cancer cells expressing different levels of erbB2. To extend our understanding of the molecular mechanisms of cell death triggered by VE analogues, we investigated apoptotic pathways induced by the agents, one of which is the mitochondrial pathway. Generation of reactive oxygen species (ROS) preceded mitochondrial destabilization and execution of apoptosis, as evidenced by the anti-apoptotic effects of exogenous superoxide dismutase (SOD) and mitochondrially targeted coenzyme Q (MitoQ). Dissipation of the mitochondrial potential (ΔΨm) was followed by cytochrome c (Cyt c) and Smac/Diablo re-localization and caspase-dependent cleavage of death substrate. The other pathway studied was the survival (anti-apoptotic) Akt/NFκB signalling pathway. We document that α-TOS inhibited nuclear translocation of the subunit p65 of the transcriptional factor nuclear factor-κB (NFκB) in erbB2-over-expressing breast cancer cells, which is expected to result in inactivation of NFκB. A synergism of α- TOS and the tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) in apoptosis induction was confirmed in experiments with breast cancer cells with high and low expression of erbB2. To verify the efficacy of VE analogues in killing cancer cells in vivo, we also used the FVB/N c-neu transgenic mice with spontaneous breast carcinomas (high erbB2) and the human breast cancer MCF7 xenograft model (low erbB2) to investigate the effect of α-TOS on cancer progression. We show that α-TOS significantly inhibited tumour growth compared to the controls in both animal models.