【Abstract】 Objective To investigate the mechanism of miR-135b-5p on the sensitivity of MCF-7 / DOXR cells to doxorubicin by regulating XBP1. Methods The expression level of XBP1 protein was detected by Western blot. The expression level of XBP1 mRNA in breast cancer cells MCF-7 and breast cancer doxorubicin-resistant MCF-7/DOXR cells and the expression level of miR-135b-5p were detected by RT-qPCR. CCK-8 was applied to measure the proliferation of MCF-7/DOXR cells. Annexin-V-FITC double staining assay was applied to detect the apoptosis MCF-7/DOXR cells. Dual luciferase reporter assay was used to verify whether XBP1 was a target gene of miR-135b-5p. Results XBP1 was highly expressed in MCF-7breast cancer cells and MCF-7/DOXR cells (P＜0.05 or P＜0.01). Knockdown of XBP1 significantly inhibited MCF-7/DOXR cell proliferation and promoted apoptosis (P＜0.05 or P＜0.01). The dual luciferase reporter gene confirmed that XBP1 is a potential targets gene of miR-135b-5p, and miR-135b-5p targets down regulated the expression level of XBP1 (P＜0.05). It was further confirmed by recovery experiments that overexpression of miR-135b-5p down-regulated XBP1 and significantly inhibited MCF-7/DOXR cell proliferation and induced apoptosis (P＜0.05 or P＜0.01). Conclusion miR-135b-5p enhances sensitivity of MCF-7/DOXR cells to doxorubicin by down regulating XBP1.