Background. Mesenchymal stem cells (MSCs) are multipotent stem cells that have immunomodulary properties and that produce a variety of hematopoiesis-stimulating cytokines. They can be expanded in vitro at clinical scale and are currently used in several pre-clinical and clinical studies for supporting hematopoiesis and/or controlling graft vs. host disease after hematopoietic stem cell transplantation, for tissue engineering or as gene therapy vehicles. MSCs have also been shown to have the capacity to home in vivo to tumor sites and to support tumor development by integrating into the tumor stroma. Aims. In this study we examined whether in vitro expanded bone-marrow-derived MSCs can be recruited by multiple myeloma (MM) cells and at which level MSCs directly affect growth and survival of MM cells. Methods. Human MSCs and murine MSCs were isolated from bone marrow aspirates of human voluntary donors and C57BL/KaLwRij mice, respectively. in vitro and in vivo migration assays were used to evaluate the migration ability of MSCs towards MM cells. Human stroma-dependent myeloma cells (MM5.1) , stroma-independent myeloma cells (RPMI8226) or murine stroma-dependent myeloma cells (5T33MMvv) and stroma-independent myeloma cells (5T33MMvt) were co-cultured with human or murine MSCs. The effect on proliferation/apoptosis was evaluated. Expression of proteins involved in cell cycle progression and apoptosis was tested by Western blot analysis. in vivo co-engraftment experiments (MSCs + MM cells) in the 5T33MM model were performed to confirm in vitro findings. Results. in vitro migration assays revealed that both human and murine MSCs can be attracted by MM cells. Accordingly we found by fluorescence microscopic analysis of paraffin sections from various tissues that DiI-labeled murine MSCs home in the 5T33MM model after intraveneous injection to MM-invaded organs (tibia and spleen) at a higher level as compared to the naive mice. We further identified CCL25 was the most important MM cell-produced chemokine that triggers MSC migration through the CCR9 receptor. By co-culturing MM cells and MSCs, we found that MSCs favor the proliferation of stroma-dependent MM cells by secreting soluble factors and by cell-cell contact, which was confirmed by co-engraftment experiments in the in vivo 5T33MM mouse model. We also demonstrated that MSCs protect in vitro MM cells against spontaneous and Bortezomib-induced apoptosis. Moreover we found that after co-culturing with mMSCs, murine MM cells show an up-regulation of phosphorylated AKT and ERK, accompanied with increased CyclinD2, CDK4 and Bcl-XL, and decreased cleaved caspase-3 and PARP. Conclusions. In conclusion our results provide evidence that reciprocal interaction between MSC and MM cells induce chemoattraction of MSCs by MM cells resulting in MSC-mediated stimulation of MM cell survival and proliferation. As precursors of the bone marrow stroma, MSCs seem to play an active role in the pathophysiology of this disease. Our data also suggest that therapeutical infusion of normal donor-derived MSCs should be considered with caution as these adult stem cells might enhance tumor progression in vivo resulting/contributing in disease relapse after MSC-based cytotherapy.