Previous work from our group has shown that Cd38−/− mice develop a milder pristane-induced lupus disease than WT or Art2−/− counterparts, demonstrating a new role for CD38 in promoting aberrant inflammation and lupus-like autoimmunity via a Transient Receptor Potential Melastatin 2 (TRPM2)-dependent apoptosis-driven mechanism. In this study we asked whether CD38 may play a role in the expression and function of regulatory B cells (IL-10-producing B cells or B10 cells). In pristane-treated mice the frequency of spleen CD19+CD1dhiCD5+ B cells, which are highly enriched in B10 cells, was significantly increased in Cd38−/− splenocytes compared to WT, while the frequency of peritoneal plasmacytoid dendritic cells (pDCs), which are major type I Interferon (IFN) producers, was greatly diminished. The low proportion of pDCs correlated with lower amounts of IFN-α in the peritoneal lavage fluids of the Cd38−/− mice than of WT and Art2−/− mice. Functional ex vivo assays showed increased frequencies of IL-10-producing B cells in Cd38−/− splenocytes than in WT upon stimulation with an agonist anti-CD40 mAb. Overall these results strongly suggest that Cd38−/− mice are better suited than WT mice to generate and expand regulatory B10 cells following the appropriate stimulation.