Both Frondoside A and Cucumarioside A2-2 are extracts from sea cucumbers. Frondoside A is a pentaoside having an acetyl moiety at the aglycon ring and xylose as a third monosaccharide residue. Cucumarioside A2-2 is a pentaoside having glucose as a third monosaccahride unit. The effects of Frondoside A and A2-2 for cell death-inducing capability with close attention paid to structure–activity relationships were compared. Both Frondoside A and A2-2 strongly induced apoptosis of leukemic cells. Frondoside A-induced apoptosis was more potent and rapid than A2-2-induced apoptosis. A2-2-induced but not frondoside A-induced apoptosis was caspase-dependent. This suggests that holothurians may induce apoptosis of leukemic cells caspase-dependently or -independently, depending on the holothurian structure.