The objective of the present study was to investigate the effects of saponins from the anomalous fruits of Gleditsia sinensis on mast cell degranulation triggered by compound 48/80 and to determine possible structure-activity relationships. Among the eleven saponins tested, four effectively inhibited β-hexosaminidase release from rat peritoneal mast cells. Studies of structureactivity relationships indicated that saponins with an aglycone of echinocystic acid instead of oleanolic acid were more effective. A sugar chain at C-3 was essential for the inhibitory effects, and a single sugar chain was the most effective. The length and structures of the oligosaccharide chain at C-28 were also critical for the activity of the compounds, and introduction of monoterpene units to the oligosaccharide chain substantially decreased the activity. To gain insight into the mechanisms responsible for preventing mast cell degranulation, the effects of saponins on intracellular cAMP were examined. After preincubation with mast cells for different times, the four active saponins significantly increased the intracellular cAMP content. These findings suggested that the four saponins might be the active constituents of the anomalous fruits of G. sinensis for antiallergic activities, and they prevented mast cell degranulation probably by elevating intracellular cAMP levels.