Saponins enhance the cytotoxicity of the type I ribosome-inactivating protein (RIP-I) saporin. In the present study, the synergistic cytotoxicity of nine newly isolated gypsogenin-containing saponins from Gypsophila trichotoma in combination with RIP-I was evaluated in vitro and used to derive a quantitative structure – activity relationship (QSAR). The QSAR model distinguished two important structural features of the studied saponins necessary for their cytotoxicity enhancing activity: the branched trisaccharide moiety attached to C-3 should contain one xylose residue instead of an arabinose and the branched tetrasaccharide at C-28 should contain one acetyl group attached to the glucose residue.