Bone resorption is regulated by the immune system, where receptor activator of nuclear factor (NF)kappaB ligand (RANKL), a new member of the tumor-necrosis factor family, may contribute to pathological conditions. Due to the role of RANKL in the maturation of monocyte-derived osteoclasts, we hypothesized that RANKL could exert chemotactic properties toward monocytic cells. Our results demonstrate that RANKL induces the migration of MonoMac-6 monocytic cells as well as human freshly isolated total peripheral blood mononuclear cells (PBMC) and CD14+ purified PBMC. RANKL induces the migration of MonoMac-6 cells in a dose-dependent manner and with an efficacy similar to MCP-1. After an 8-h incubation, the soluble form of RANKL (sRANKL) started to exhibit a chemoattractive effect on MonoMac-6 cells, with an increased effect observed up to 24 h. RANKL elicits an additive chemotactic effect to MCP-1. Furthermore, addition of the RANKL decoy receptor osteoprotegerin in the lower well or RANKL in the upper well abrogates the RANKL-induced migration of MonoMac-6 cells, hallmarking a true specific activity. RNase protection assay experiments indicate that exposure of MonoMac-6 cells to RANKL had no significant effect on the expression of a variety of chemokines, known to attract monocytes. This study provides evidence that RANKL behaves as a chemotactic factor for monocytic cells, emphazing the cross-talk between bone and immune systems.