B?cells contribute to chronic inflammatory conditions as source of antibody-secreting plasma cells and as antigen-presenting cells activating T?cells, making anti-CD20-mediated B?cell depletion a widely used therapeutic option. B?cells or B?cell subsets may, however, exert regulatory effects, while to date, the immunological and/or clinical impact of these observations remained unclear. We found that in multiple sclerosis (MS) patients, B?cells contain regulatory features and that their removal enhanced activity of monocytes. Using a co-culture system, we identified B?cell-provided interleukin (IL)-10 as key factor in controlling pro-inflammatory activity of peripheral myeloid cells as well as microglia. Depleting B?cells via anti-CD20 in a mouse model of MS unleashed the activity of myeloid cells and microglia and accelerated disease severity; in contrast, adoptive transfer of IL-10-providing B?cells restored in vivo control of central nervous system (CNS) macrophages and microglia and reversed clinical exacerbation. These findings suggest that B?cells exert meaningful regulatory properties, which should be considered when designing novel B?cell-directed agents.