Interleukin 10 (IL-10)–producing B cells (regulatory B cells [Bregs]) regulate autoimmunity in mice and humans, and a regulatory role of IL-10–producing plasma cells has been described in mice. Dysfunction of B cells that maintain homeostasis may play a role in the pathogenesis of chronic graft-versus-host disease (cGVHD) after allogeneic stem cell transplantation. Here, we found a relation between decreased Breg frequencies and cGVHD severity. An impaired ability of B cells to produce IL-10, possibly linked to poor signal transducer and activator of transcription 3 and extracellular signal-regulated kinase phosphorylation, was found in patients with active cGVHD. IL-10 production was not confined to a single B-cell subset, but enriched in both the CD24^hiCD27⁺ and CD27^hiCD38^hi plasmablast B-cell compartments. In vitro plasmablast differentiation increased the frequency of IL-10–producing B cells. We confirmed that allogeneic transplant recipients had an impaired reconstitution of the memory B-cell pool. cGVHD patients had less CD24^hiCD27⁺ B cells and IL-10–producing CD24^hiCD27⁺ B cells. Patients with cGVHD had increased plasmablast frequencies but decreased IL-10–producing plasmablasts. These results suggest a role of CD24^hiCD27⁺ B-cell and plasmablast-derived IL-10 in the regulation of human cGVHD.