The ability of NK cells to induce differentiation of B lymphocytes to IgM secretion in vitro has been investigated. Homogeneous preparations of NK cells obtained from IL-2 propagated splenocytes from SCID mice were found to have the ability to induce resting B lymphocytes to proliferate and secrete significant amounts of IgM. The induction is greatly enhanced by the presence of both IL-2 and IL-5 and does not require T lymphocytes or adherent cells in the responding population. Cell contact between the two populations is not necessary suggesting that the effect is mediated by soluble factor(s) which can be produced even by irradiated NK cells. Because the activity cannot be replaced by either r-tau-IFN or tumor necrosis factor-alpha or inhibited by antibodies to these lymphokines, a novel NK cell-derived factor(s) may be involved. The implications of this interaction between NK cells and B lymphocytes are discussed.