The apoptotic signaling pathway is obviously disordered in systemic lupus erythematosus (SLE). Concurrent occurrence of induced apoptotic cell death and altered phagocytosis promotes autoantigen production, which leads to the biosynthesis of autoantibodies and autoimmune disorders. Natural IgM (nIgM) is important in clearing apoptotic cells and preventing them from triggering deleterious autoimmunity. B-1- and innate-like B- (ILBs) cells are the main nIgM producers. Human CD27+IgD+B cells (un-switched memory B cells) are considered ILBs. However, their functional properties in SLE remain undefined. Here, individuals with SLE showed markedly reduced CD27+IgD+B cell amounts. Moreover, these cells had altered function in terms of natural antibody-like IgM production. CD27+IgD+B cells also showed negative correlations with clinical and immunological properties in SLE patients. Following effective treatment achieving SLE remission, CD27+IgD+B cell amounts were restored. Jointly, these findings suggest that CD27+IgD+B cell dysfunction potentially contributes to the exacerbation of SLE, and modulating their features may represent a powerful tool for treating this persistent disease.