In the present study, effects of various hederagenin monodesmosides isolated from the stem bark of Kalopanax pictus NAKAI, such as hederagenin, δ-hederin, kalopanaxsaponin A, kalopanaxsaponin I, and sapindoside C, have been evaluated on lipopolysaccharide (LPS)-induced nitric oxide (NO), prostaglandin E₂ (PGE₂) and tumor necrosis factor-α (TNF-α) release by the macrophage cell line RAW 264.7. Among the tested monodesmosides, kalopanxsaponin A was the most potent inhibitor of NO production, and it also significantly decreased PGE₂ and TNF-α release. Consistent with these observations, the expression level of inducible NO synthase (iNOS) and cyclooxygenase (COX)-2 enzyme was inhibited by kalopanxsaponin A in a concentration-dependent manner. Thus, this study suggests that kalopanaxsaponin A-mediated inhibition of iNOS, COX-2 expression, and TNF-α release may be one of the mechanisms responsible for the anti-inflammatory effects of the stem bark of Kalopanax pictus NAKAI.