Abstract Purpose Panax ginseng (P. ginseng) root is a complementary and alternative medicine (CAM) typically used in traditional Asian medicine. We have reported that oral consumption of the P. ginseng aqueous extract (PgE) by mice augments natural killer (NK) cell activity, which is critical for immune surveillance against tumors. In this study, we further examined the effect of oral consumption of PgE on human NK cell phenotypes and cytotoxicity. Methods Here we examined the effects of oral intake of PgE (1000 mg per day, as recommended by the manufacturer) for two weeks on NK cell activity in ten human volunteers in a cross-over trial. Results No adverse reactions were observed in any volunteers, although two dropped out due to personal reasons. Oral intake of 1000 mg of PgE for two weeks did not affect the size of the NK cell population or CD56 expression on NK cells. However, NK cell cytotoxicity was significantly augmented in five out of eight subjects. When the NK cell response was divided into two categories (significantly increased or stable/decreased), Fisher's exact test and the χ2 test demonstrated a significant difference in NK cell cytotoxicity between the PgE-treated and placebo groups. Conclusion Oral intake of 1000 mg of PgE for two weeks significantly augmented NK cell cytotoxicity over that observed with the placebo.