Resistance to chemotherapy represents a major cause for treatment failure in multiple myeloma (MM). Herein, this study was conducted to explore the effect of SDF‐1/CXCR4 and interleukin‐6 (IL‐6) in MM cell adhesion‐mediated chemoresistance. Enzyme‐linked immunosorbent assay was applied to detect expressions of SDF‐1α and IL‐6 in MM patients and healthy controls. RPMI‐8226 cells and isolated bone marrow stromal cells (BMSCs) were stimulated using recombinant SDF‐1α and IL‐6. Effect of cocultured BMSCs and RPMI‐8226 cells on chemosensitivity and apoptosis of RPMI‐8226 cells was analyzed. Effect of doxorubicin on the adhesion rate of RPMl‐8226 cells to BMSCs was analyzed by calcitonin test. Effect of SDF‐1α‐induced upregulation of IL‐6 on chemotherapeutic resistance and apoptosis of RPMI‐8226 cells in adhesion state was analyzed. Cell adhesion model was treated with recombinant protein SDF‐1α and phosphoinositide 3‐kinase (P13K) inhibitor Wortmarmin. The levels of P13K and protein kinase B (AKT) and its phosphorylation as well as the expression of IL‐6 were analyzed. SDF‐1α was positively correlated with IL‐6. Recombinant human SDF‐1α increased IL‐6 expression and induced IL‐6 secretion in a time‐ and dose‐dependent manner in BMSCs, which was inhibited by IL‐6 and SDF‐1α neutralizing antibodies. Coculture of MM cells with BMSCs increased the drug resistance and inhibited the apoptosis on MM cells. SDF‐1α‐induced IL‐6 upregulation mediates chemoresistance and apoptosis of RPMI‐8226 cells in adhesion state. SDF‐1α may up‐regulate the expression of IL‐6 by activating the P13K/AKT signaling pathway. SDF‐1/CXCR4 may up‐regulate the expression of IL‐6 through the activation of the P13K/AKT signaling pathway, thereby affecting the chemoresistance mediated by adhesion in MM cells.