Ginsenoside Rg1 is one effective anticancer and antioxidant constituent of total saponins of Panax ginseng(TSPG), which has been shown to have various pharmacological effects. Our previous study demonstrated thatRg1 had anti-tumor activity in K562 leukemia cells. The aim of this study was designed to investigate whetherRg1 could induce apoptosis in TF-1/Epo cells and further to explore the underlying molecular mechanisms. Herewe found that Rg1 could inhibit TF-1/Epo cell proliferation and induce cell apoptosis in vitro in a concentrationand time dependent manner. It also suppressed the expression of EpoR on the surface membrane and inhibitedJAK2/STAT5 pathway activity. Rg1 induced up-regulation of Bax, cleaved caspase-3 and C-PAPR protein anddown-regulation of Bcl-2 and AG490, a JAK2 specific inhibitor, could enhance the effects of Rg1. Our studiesshowed that EpoR-mediated JAK2/STAT5 signaling played a key role in Rg1-induced apoptosis in TF-1/Epocells. These results may provide new insights of Rg1 protective roles in the prevention a nd treatment of leukemia.