The resistance of tumor cells to apoptosis-inducing anticancer agents is regarded as a major impediment for the treatment of cancer patients. This study aimed to examine the possibility whether a necrosis-inducing peptide containing the mitochondria-targeting domain (MTD) of NOXA kills tumor cells that are resistant to apoptosis-inducing anticancer agents. To examine this possibility， we established doxorubicin-resistant (Dox-Res) cells by treating CT26 cells with increasing amounts of doxorubicin. The apoptosis resistance of the Dox-Res CT26 cells was confirmed by measuring the cell viability and activation of caspases. We showed that the MTD-containing peptide fused to eight arginine residues (R8:MTD)， a necrosis-inducing peptide， induced necrosis in the Dox-Res CT26 cells， together with a cytosolic calcium spike， reactive oxygen species production， and the release of high mobility group box 1 into the media. Moreover， we demonstrated the killing effect of R8:MTD in tumor tissues generated using the Dox-Res CT26 cells in a mouse model. Therefore， our results suggest that MTD-containing peptides may provide an alternative tool for the elimination of relapsed tumor cells that are not responsive to apoptosis-inducing anticancer agents.