We examined the effect of both CD3-CD16(Leul la)+CD56(NKH1,Leu19)+ non-T lineage natural killer (NK) cells and CD3+CD8+CD16-CD56+ T lineage NK cells on B cell proliferation and differentiation. Fluorescence-activated cell sorter (FACS) purified CD16+CD56+ cells suppressed pokeweed mitogen (PWM) induced immunoglobulin synthesis. However, the T lineage NK cells tended to suppress immunoglobulin synthesis only when CD8+ cells were eliminated from the culture, and even then CD16+ NK cells suppressed antibody production more efficiently than did CD3+CD8+ NK cells. CD16+ NK cells did not suppress B cell proliferative responses to several mitogens. CD16+ NK cells from patients with Wiskott-Aldrich syndrome, who showed the high percentage of CD16+ NK cells, did not inhibit immunoglobulin synthesis. We concluded that non-T NK cells are the major immunoregulatory NK cells for immunoglobulin synthesis in normal immune systems, and that they suppress immunoglobulin synthesis through their action on B cell differentiation.