Abstract The immune and the skeletal system are tightly interconnected, and B lymphocytes are uniquely endowed with osteo-interactive properties. In this context, receptor activator of NF-κB (RANK) ligand (RANKL) plays a pivotal role in lymphoid tissue formation and bone homeostasis. Although murine models lacking RANK or RANKL show defects in B cell number, the role of the RANKL–RANK axis on B physiology is still a matter of debate. In this study, we have characterized in detail B cell compartment in Rankl−/− mice, finding a relative expansion of marginal zone B cells, B1 cells, and plasma cells associated with increased Ig serum levels, spontaneous germinal center formation, and hyperresponse to CD40 triggering. Such abnormalities were associated with an increased frequency of regulatory B cells and augmented B cell–derived IL-10 production. Remarkably, in vivo IL-10-R blockade reduced T cell–triggered plasma cell differentiation and restrained the expansion of regulatory B cells. These data point to a novel role of the RANKL–RANK axis in the regulation of B cell homeostasis and highlight an unexpected link between IL-10 CD40 signaling and the RANKL pathway.