〔Abstract〕 Objective To investigate the role of miR-15 a-5 p in DOX resistance of lung cancer cells, and to elucidate the relationship between miR-15 a-5 p and DOX resistance. Methods miR-15 a-5 p inhibitor and miR-15 a-5 p mimics were used to transfect A549 and A549/DOX resistant cells(A549/D). MTT assay was used to detect cell viability, flow cytometry was used to detect cell apoptosis, Western blot was used to detect the expression of EMT related protein and P53 protein, and QRT PCR was used to detect the expression of miR-15 a-5 p. The potential target genes of miR-15 a-5 p were analyzed by bioinformatics prediction, dual luciferase reporter. A549/D cells were used to establish the xenograft tumor model in nude mice, and the effect of miR-15 a-5 p overexpression on DOX in vivo was analyzed. Results MTT analysis showed that the knockdown of miR-15 a-5 p increased the cell viability of A549 cells(IC50value: 8.86±0.32 μmol/L), and the overexpression of miR-15 a-5 p decreased the cell viability of A549/D cells(IC50value: 1.92±0.11 μmol/L). Blocking miR-15 a-5 p in A549 cells reduced apoptosis(P<0.001), and increasing the expression of miR-15 a-5 p in A549/D cells promoted apoptosis(P<0.001). The role of DOX in regulating the EMT was reversed by the transfection of miR-451 a inhibitor through Western blot. Bioinformatics prediction showed that there was a specific binding site between P53 and miR-15 a-5 p. miR-15 a-5 p inhibition reduced the expression of P53 protein in A549 cells(P<0.001), and miR-15 a-5 p over-expression increased the expression of P53 protein in A549/D cells(P<0.01). In vivo experiments showed that combination of agomir-miR-15 a-5 p and DOX could reduce the tumor volume and the expression level of N-cadherin, and enhance the expression levels of P53 and E-cadherin. Conclusion miR-15 a-5 p over-expression may inhibit EMT by targeting P53 and enhance the sensitivity of lung cancer cells to DOX therapy.