Multidrug resistance (MDR) is the main obstacle in breast cancer chemotherapy, a reversal reagent with high reversal effect but low toxicity is the hotpot issue at present. The antidepressant fluoxetine (FLX) is a new highly effective chemosensitizer; however, the possible mechanism of FLX in reversal of MDR is unclear. In this study, the effect of FLX on MDR mediated by apoptosis was researched in resistant/sensitive breast cancer cells, which treated by FLX/adriamycin (ADM)/paclitaxel (PTX) alone or FLX-ADM, FLX-PTX combination. Apoptosis assay demonstrated that FLX combined with ADM enhanced the proportion of apoptosis remarkably in MCF-7/ADM but not MCF-7 cells; however, increased the apoptosis rates in both cells when FLX-PTX combination. Results of apoptosis proteins assay showed a upgrade of p53 and a downgrade of Bcl-2 level by FLX-ADM or FLX-PTX combinations in both cells. Our findings indicated that by synergism with anticancer drugs, FLX modulation of apoptosis via targeting p53 and Bcl-2 expression, FLX reverse the breast cancer cell's resistance and enhance the chemosensitivity to ADM and PTX.