The effects of IL-6 and IL-2 on highly purified, human peripheral blood large granular lymphocytes (LGL) were investigated and compared. IL-6 enhanced LGL NK activity in a dose-dependent manner against K562, however IL-2 was a more potent stimulus of LGL NK function. Neither IL-2 nor IL-6 increased LGL cytotoxic potential in a parallel estimation of heteroconjugated antibody (anti-CD16 x anti-nitrophenyl mAb)-dependent cytotoxicity against nitrophenyl-modified YAC. Unlike IL-2, IL-6 did not significantly induce LGL lymphokine-activated killer activity, LGL proliferation, or LGL lymphokine production. In particular, IL-6 did not stimulate detectable LGL IL-2 production or IL-2R modulation, and mAb to the p75 IL-2R had no effect on IL-6 induction of LGL NK activity. Therefore, in the absence of T cells, IL-6 provided an IL-2-independent signal to LGL that resulted in augmentation of their NK activity without stimulating their proliferation or other LGL functions.