Bisphosphonates have recently been introduced in the therapeutic armamentarium for the long-term treatment of patients with multiple myeloma (MM). These pyrophosphate analogs not only reduce the occurrence of skeletal-related events but also provide patients with a clinical benefit and improve the survival of some of them. We investigated the effects of two bisphosphonates, pamidronate and zoledronate, on both myeloma cells and bone marrow stromal cells (BMSCs). We show here that both bisphosphonates induce both myeloma cell and BMSC apoptosis. Furthermore, at lower concentrations, they induce a significant inhibition (40% and 60%, respectively) of the constitutive production of interleukin-6 (IL-6) by BMSCs. We have recently shown that BMSCs produce MMP-1, the major metalloproteinase involved in the initiation of bone resorption, production up-regulated by IL-1beta. Here, we demonstrate that zoledronate significantly inhibits MMP-1 production by BMSCs stimulated with IL-1beta more efficiently than pamidronate. However, zoledronate and to a lesser extent pamidronate are responsible for an up-regulation of MMP-2 secretion by BMSCs. MMP-2 is involved both in bone resorption and in the metastatic process. In conclusion, the apoptosis of myeloma cells and BMSCs and the inhibition of both IL-6 and MMP-1 production induced by bisphosphonates, mainly zoledronate, could have antitumoral effects in patients with MM. However, the up-regulation of MMP-2 secretion observed in vitro suggests a putative risk of tumor cell dissemination in vivo when using these new potent bisphosphonates. This potentially deleterious effect could be abolished by combining bisphosphonates with metalloproteinase inhibitors.