ADAM-9, a member of the adisintegrin and metalloproteinase family, contains both metalloproteinase and disintegrin domains. Myeloma cell lines express ADAM-9; however, its function and role in the pathophysiology of multiple myeloma is unknown. The aim of this study was to establish whether primary myeloma cells express ADAM-9, whether ADAM-9 regulates IL-6 production in human osteoblasts (hOBs), whether ADAM-9 interacts with specific integrin heterodimers, and the identity of downstream signaling pathways. Primary myeloma cells demonstrated increased expression of ADAM-9 (P < .01). ADAM-9 promoted a 5-fold increase in IL-6, but not IL-1β mRNA, and a dose- and time-dependent increase in IL-6 production by hOBs (P < .01). IL-6 induction was inhibited by an antibody to the α_vβ₅ integrin (P < .01) but not by antibodies to other integrin heterodimers. ADAM-9 was shown to bind directly to the α_vβ₅ integrin on hOBs. Antibodies to ADAM-9 and α_vβ₅ integrin inhibited myeloma cell–induced IL-6 production by hOBs (P < .01). Furthermore, inhibitors of p38 MAPK and cPLA₂, but not NF-κB and JAK2, signaling pathways inhibited ADAM-9–induced IL-6 production by hOBs (P < .01). These data demonstrate that ADAM-9, expressed by myeloma cells, stimulates IL-6 production in hOBs by binding the α_vβ₅ integrin. This may have important consequences for the growth and survival of myeloma cells in bone.