To investigate the effects of the 20(S)-ginsenoside Rh2 [Rh2(S)]on cell proliferation, histone deacetylase 1 (HDAC1) and HDAC2 activity, and expression of cyclin in human erythroleukemia K562 cells.The K562 cells were treated with Rh2(S) at various concentrations (10-80 μmol/L). Cell proliferation activity was detected by CCK-8 assay. Flow cytometry (FCM) was used to detect cell cycle and apoptotic changes. The HDAC activity of cells was measured by chemical colorimetry. The protein expressions of HDAC1, HDAC2, cyclin D1, CDK4, p16INK4A and p21 after 48 hour-treatment of Rh2 (S) (10, 20, 40, 60 μmol/L) were examined by Western blotting.The proliferation of K562 cells was inhibited by Rh2 (S) (20-80 μmol/L) in dose-and time-dependent manner. FCM analyses revealed that the number of the K562 cells treated with 60 μmol/L Rh2(S) was arrested in G0/G1 phase. The apoptosis rates of K562 cells were respectively (8.09±0.86)%, (9.44±0.53)% and (22.80±2.16)% after induced by 20, 40, 60 μmol/L Rh2(S), which showed statistically significant difference (P<0.05) compared with the control group (2.63±0.14)%. HDAC activity of the cells treated with Rh2(S) (40, 60 μmol/L) was reduced. Western blotting showed that the expressions of HDAC1, HDAC2, cyclin D1 and CDK4 decreased after induced by Rh2(S), and p16INK4A, p21 proteins were enhanced significantly.The Rh2(S) can inhibit the proliferation of K562 cells and induce its cycle arrest and apoptosis through inhibiting HDAC1 and HDAC2 activity, down-regulating the expression of cyclin D1 and activating p16INK4A and p21.