Abstract: OBJECTIVE To investigate the mechanism of doxorubicin-schisandrin B co-delivery liposomes(DSCL) to overcome multidrug resistance(MDR). METHODS DSCL were prepared. The K562/DOX cells were chosen as the model cells. The low temperature test, Endocytosis inhibitors (chloroquine, sodium azide, and mannitol) test were carried out on K562/DOX cells. And P-gp expression and apoptosis were detected by flow cytometry. RESULTS The uptake of DSCL was energy-dependent and was influenced by temperature, and endocytosis inhibitors, such as chloroquine, sodium azide and mannitol, could decrease significantly accumulation of DOX. The flow cytometry result revealed that the expression of P-gp of K562/DOX cells was significantly inhibited after treatment with DSCL, and it showed DSCL induced a regulated apoptotis in cells. CONCLUSION DSCL were uptaken through the endocytosis of energy-dependent. It is proposed the mechanism of DSCL to overcome multidrug resistance was a dual strategy by inhibiting the expression of P-gp and promoting apoptotis.