Abstract We previously reported that human NK cells express G2A and they respond to LPC. Here, we report that oxidized lipids such as 9-R-HODE, 9-S-HODE and 13-R-HODE, as well as LPC induced the in vitro chemotaxis of human NK cells, although with variable efficacies. The chemotactic effects of these lipids were inhibited by prior treatment of NK cells with pertussis toxin (PTX). 9-S-HODE, 9-R-HODE and LPC optimally induced the influx of intracellular Ca2+ in NK cells. Addition of 9-S-HODE prior to the addition of LPC inhibited more than 50% of the effect of LPC, whereas addition of LPC prior to the addition of 9-S-HODE completely inhibited the effect of the latter lipid. Also, there was a complete reciprocal desensitization among 9-R-HODE and LPC on the influx of intracellular Ca2+. Further analysis showed that the four lipids did not affect NK cell lysis of tumor target cells. 9-R-HODE but not any other lipid increased the percentages of NK cells producing IFN-γ and is the only lipid that enhanced the release of this cytokine by these cells. In conclusion, we provide novel evidence showing that oxidized lipids and LPC exert important functions for cells of innate immune system.