Inspite of effective treatment with imatinib (IM), chronic myeloid leukemia (CML) is still an incurable disease. Some patients became refractory because of IM resistance. Bone marrow mesenchymal stem cells (BMSCs) have been implicated a role in promoting CML cells' resistance against IM treatment. The detailed molecular mechanisms, however, remain largely unknown. In this study, we found that BMSCs increased the expression of FZD7 and activated Wnt/β-catenin signaling pathway in CML cells. BMSCs from CML patients showed increased efficiency to accelerate CML cell proliferation, enhance the drug resistance of K562 cells and up-regulate the expression of FZD7. Antagonism of FZD7 expression by shRNA significantly suppressed proliferation and increased IM sensitivity of CML cells co-cultured with BMSCs cells. Our findings suggest that FZD7, involved in canonical Wnt signaling pathway, plays a critical role in mediating BMSCs-dependent protection of CML cells, and potentially provide a novel therapeutic target for CML.