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Holothurian triterpene glycosides are known to possess multiple biological activities. Here we show that cucumarioside A_2-2 from the Far-Eastern edible holothurian Cucumaria japonica possesses potent immunomodulatory properties. The present studies were done to determine if cucumarioside A_2-2 would affect macrophage adhesion, spreading, and motility. Resident peritoneal macrophages, collected from BALB/c mice, were exposed in vitro to low concentrations of cucumarioside A_2-2 and compared with appropriate controls. Results indicate that 0.02 μg/mL cucumarioside A_2-2 significantly enhanced macrophage morphology parameters and behavior. The glycoside stimulated these parameters by increasing the number of cells with increased adhesion properties as well as the spreading reaction and motility velocity by at least almost twofold. The data are discussed in terms of possible mechanisms underlying the immunomodulatory properties of cucumarioside A_2-2.