NK cells are an important component of innate immunity, and they can promote CTL and Th1 cell development and macrophage activation via cytokines. TGF-β is believed to be an important immunoregulatory molecule, and for this reason several TGF-β inhibitors are currently in clinical development. However, the modulation of specific innate immune responses by endogenous human TGF-β remains unclear. In this study, we demonstrate that blocking the action of endogenous TGF-β resulted in an increase in both the percentage of responding NK cells and the amount of IFN-γ produced by human NK cells when stimulated by monokines and TLR agonists. Blocking endogenous TGF-β resulted in significant NK cell IFN-γ production under suboptimal stimulation conditions. Our findings also suggest that TGF-β associated with other blood cells may be involved in limiting NK cell activation. Thus, inhibiting endogenous TGF-β provides a means to shift NK cell activation and promote cellular immunity.