Metadherin (MTDH) is highly expressed in many tumors and is involved in the proliferation, metastasis and drug resistance of tumor cells by regulating multiple signaling pathways. Our previous studies demonstrated that MTDH is overexpressed in diffuse large B cell lymphoma (DLBCL) and involved in apoptosis resistance, in part, via Wnt signaling. Here, we investigated the role of MTDH in the chemo-sensitivity of DLBCL. The study was performed in the DLBCL cell line LY8 to investigate the relationship between MTDH expression and doxorubicin (DOX) sensitivity in DLBCL. A MTDH interference model was developed in LY8 cells by transfected with lentivirus which is carrying MTDH interference sequence. Western blot was used to detect the protein expression. A CCK-8 assay was used to evaluate cell proliferation. The results showed that DOX treatment had no effect on the intracellular MTDH expression of LY8 cells. The proliferation of LY8 cells was inhibited after MTDH interference. MTDH interference increased the DOX sensitivity in the LY8 cell lines. The results suggested that MTDH is a potential therapeutic target in DLBCL, and it cooperates with DOX in treatment of DLBCL.