An enzyme-linked immunospot assay was used to quantitate the number of autoantibody-secreting B cells in the peripheral blood of 67 patients with systemic lupus erythematosus. These patients had 1.5-4-fold more lymphocytes secreting IgG and IgM per million peripheral blood lymphocytes than did normal controls. There was a concomitant increase in the number of B cells secreting antibodies reactive with a diverse panel of foreign and self antigens (including actin, myosin, tri-nitrophenylated keyhole limpet hemocyanin, ovalbumin, and retroviral gp160). By comparison, the number of B cells producing anti-DNA antibodies was increased disproportionately. The magnitude of this anti-DNA response correlated significantly with disease activity. Thus, B cell activation in human systemic lupus erythematosus had characteristics of both generalized (polyclonal) B cell activation and (auto)antigen-specific immune stimulation.