IL-21 promotes plasma cell (PC) differentiation while BAFF promotes B-cell survival. Here, we report that IL-21 synergizes with BAFF to elicit BLIMP-1 induction, PC differentiation and IgG production from a novel population of human splenic memory B cells. These human marginal zone analogue B cells are exquisitely sensitive to IL-21 and BAFF in the absence of further co-stimulation. The ability of IgG+ marginal zone analogue to respond specifically and exclusively to IL-21 and BAFF demonstrates that they are uniquely poised to respond to antigen-independent signals and differentiate into IgG-producing PC, thereby replenishing serologic memory. Importantly, peripheral blood B cells from a portion of patients with systemic lupus erythematosus and rheumatoid arthritis were highly responsive to stimulation with IL-21 and BAFF. These data suggest that IL-21 and BAFF may be capable of inducing PC differentiation from memory B cells with autoreactive specificities and thereby contribute to autoimmunity.