In this study we investigated the anti-inflammatory effects of an icariin derivative (3,5-dihydroxy-4'-methoxy-6 '',6 ''-dimethyl-4 '',5 ''-dihydropyrano[2 '',3 '':7,8]-flavone). We found that this icariin derivative inhibits tumor necrosis factor-alpha (TNF-alpha) production, inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) mRNA expression, and protein expression in lipopolysaccharide (LPS) stimulated RAW264.7 macrophages. It also alleviates paw edema induced by carrageenan in mice. To clarify the molecular mechanisms underlying these anti-inflammatory effects, we examined the effects of this compound on the phosphorylation of mitogen-activated protein kinase (MAPK), phosphorylation of inhibitory kappaBalpha (I kappa B alpha), and nuclear translocation of p65 subunit of nuclear factor (NF)-kappa B, and found it suppresses the activation of p38 MAPK and inhibits translocation of NF-kappa B p65 to the nucleus through decreasing the phosphorylation of I kappa B alpha. As a result of these properties, this icariin derivative can be considered as a potential drug for inflammatory diseases.