In addition to their cytotoxic function, NK cells can either suppress or enhance Ab production. Upon activation, NK cells generally amplify Ig secretion by activated B cells. We now report that activated NK cells prepared from human peripheral blood can induce resting B cells to produce IgM and IgG. This was demonstrated by adding IL-2 or pokeweed mitogen to purified NK cells and B cells. The addition of IL-2-activated NK cells to B cells also had this effect. The responding B cells did not require activation. Moreover, following fractionation of B cells on Percoll gradients, responsive B cells were found in the high density as well as the low density fractions. The NK cell stimulatory effect was a two-step process. The first step induced B cells to respond to soluble mediators and was mediated by unstimulated NK cells, but not CD4 nor CD8 T cells. Physical contact between NK cells and B cells was required, and mAbs to CD11a and CD54 blocked this interaction. The second step was the production of as yet unidentified cytokine(s) by activated NK cells. These direct T cell-independent stimulatory effects of NK cells on B cells may be important in autoimmune and other chronic inflammatory diseases in which the suppressive effects of NK cells may be blocked.