Building on our previous report that osteoblasts and increased bone formation have a negative impact on myeloma cell growth in a subset of patients, we investigated the role of decorin, the main small leucine-rich proteoglycan (SLRP) expressed and produced by osteoblasts, in the antimyeloma effects of osteoblasts. In coculture experiments with osteoblasts, primary myeloma cell survival was significantly higher when decorin expression in osteoblasts was knocked down by short-hairpin RNA. Coculture experiments of myeloma cells and supporting osteoclasts in the presence of osteoblast-conditioned medium showed reduced myeloma cell survival, an effect that was attenuated by decorin-neutralizing antibody. Decorin overexpression in mesenchymal stem cells or use of recombinant decorin in coculture with osteoclasts reduced the ability of osteoclasts to support primary myeloma cell survival. The antimyeloma effect of decorin involved direct induction of apoptosis and activation of p21(WAF). Decorin also inhibited myeloma cell-induced tube formation and osteoclast differentiation. Decorin expression was insignificantly lower in patients' than donors' osteoblasts and slightly increased by bortezomib. Certain SLRPs are involved in the antimyeloma effect of osteoblasts directly and indirectly through inhibition of angiogenesis and osteoclastogenesis; therefore, increasing endogenous or exogenous SLRPs in myelomatous bone may help control myeloma.