A partial response or resistance to chemotherapeutic agents is considered as a main obstacle in treatmentof patients with cancer, including breast cancer. Refining taxane-based treatment procedures using adjuvantor combination treatment is a novel strategy to increase the efficiency of chemotherapy. PPM1D is a moleculeactivated by reactive oxygen species. whose expression is reported to modulate the recruitment of DNA repairmolecules. In this study we examined the impact of arsenic trioxide on efficacy of paclitaxel-induced apoptosisin paclitaxel-resistant MCF-7 cells. We also investigated the expression of PPM1D and TP53 genes in responseto this combination treatment. Resistant cells were developed from the parent MCF-7 cell line by applyingincreasing concentrations of paclitaxel. MTT assays were applied to determine the rate of cell survival. DAPIstaining using fluorescent microscopy was employed to study apoptotic bodies. Real-time RT-PCR analysis wasalso applied to determine PPM1D mRNA levels. Our results revealed that combination of arsenic trioxide andpaclitaxel elevates the efficacy of the latter in induction of apoptosis in MCF-7/PAC resistant cells. Applyingarsenic trioxide also caused significant decreases in PPM1D mRNA levels (p<0.05). Our findings suggest thatarsenic trioxide increases paclitaxel-induced apoptosis by down regulation of PPM1D expression. PPM1Ddependent signaling can be considered as a novel target to improve the efficacy of chemotherapeutic agents inresistant breast cancer cells.