A recent study has discovered that mesenchymal stem cells (MSCs) are recruited into tumors and MSC-derived exosomes in a novel mechanism of cell-to-cell communication in human cancers. Here, in this study, we explore the impact of the microRNA-208a (miR-208a)-enriched exosomes derived from bone marrow-derived mesench- ymal stem cells (BMSCs) on osteosarcoma cells. Human osteosarcoma cells MG-63and Saos-2 were exposed to BMSCs-derived exosomes treated with either miR-208a mimic or inhibitor. The MTT assay, transwell migration assay, and soft agar colony formation assay were used to evaluate the viability, migration, and clonogenicity of osteosarcoma cells. Bioinformatics analysis and dual-luciferase reporter gene assays validated the targeted relationship between miR-208a and PDCD4. Western blot assay was used to detect the expression of PDCD4 and related proteins in the ERK1/2 pathway in osteosarcoma cells. BMSCs communicated with osteosarcoma cells via exosomes. Ectopic expression of miR-208a was shown to increase the viability, migration, and clonogenicity of osteosarcoma cells. Analysis of the exosomal content identified miR-208a as a mediator of the exosomal effects on osteosarcoma cells in part via downregulation of PDCD4 and activating the ERK1/2 pathway. In summary, our study illuminates that BMSC-derived exosomal miR-208a enhances the progression of osteosarcoma. K E Y W O R D Sbone marrow-derived mesenchymal stem cells, exosome, microRNA-208a, osteosarcoma, PDCD4