Altered natural killer (NK) cell function is a component of the global immune dysregulation that occurs in advanced malignancies. Another condition associated with altered NK homeostasis is normal pregnancy, where robust infiltration with CD16 CD9+ NK cells can be identified in decidual tissues, along with a concomitant expansion of CD16 NK cells in the maternal peripheral blood. In metastatic melanoma, we identified a similar expansion of peripheral blood CD16 NK cells (median 7.4 in 41 patients with melanoma compared with 3.0 in 29 controls, P<.001). A subset of NK cells in melanoma patients also expresses CD9, which is characteristically expressed only on NK cells within the female reproductive tract. Expansion of CD16 NK cells was associated with elevated plasma transforming growth factor-beta (TGF- levels (median 20ng/ml, Spearman's =0.81,P=.015)). These findings suggest the possibility of exploring anti-TGF- therapy to restore NK function in melanoma.