Autophagy has been an emerging field in the treatment of hepatic carcinoma since anticancer therapies were shown to ignite autophagy in vitro and in vivo . Here we report that ginsenoside Rg3 and Rh2, major components of red ginseng, induce apoptotic cell death in a stereoisomer-specific fashion. The 20( S )-forms of Rg3 and Rh2, but not their respective 20( R )-forms, promoted cell death in a dose-dependent manner accompanied by downregulation of Bcl2 and upregulation of Fas, resulting in apoptosis of HepG2 cells with poly ADP ribose polymerase cleavage. The LD₅₀ value [45 µM for Rg3( S ), less than 10 µM for Rh2( S )] and gross morphological electron microscopic observation revealed more severe cellular damage in cells treated with Rh2( S ) than in those treated with Rg3( S ). Both Rg3( S ) and Rh2( S ) also induced autophagy when undergoing induced apoptosis. Inhibition of autophagy with lysosomotrophic agents significantly potentiated the cellular damage, implying a favorable switch of the cell fate to tumor cell death. Blocking intracellular calcium with 1,2-bis(2-aminophenoxy)ethane- N , N , N ′, N ′-tetraacetic acid tetrakis(acetoxymethyl ester) (BAPTA-AM) restored the cell death induced by both Rg3( S ) and Rh2( S ). Our results suggest that the 20( S )-forms of Rg3 and Rh2 in red ginseng possess more potent antitumor activity with autophagy than their 20( R )-forms via calcium-dependent apoptosis.