This study is aimed to investigate the anti-inflammatory effect of Euphorbiae kansui radix methanol extract (ERE) in lipopolysaccharide(LPS)-stimulated mouse peritoneal macrophages. Peritoneal macrophages were obtained from thioglycollate-injected Balb/c mice. Cells were stimulated with LPS or LPS plus interferon-gamma (IFN-${gamma}$) in the presence of ERE and various inflammatory markers were assayed. Finally, LPS-induced signaling molecules were measured. ERE up to $400{mu}g/m{ell}$, was not cytotoxic to ERE inhibited LPS/IFN-${gamma}$-induced nitric oxide (NO), inducible NO synthase. ERE also reduced the levels of cyclooxygenase-2 and the proinflammatory cytokines such as tumor necrosis factor-${alpha}$, interleukin(IL)-6 and IL-12. The inhibitory effect of ERE on LPS-induced $I{kappa}B{alpha}$ degradation was weak but phosphorylation of JNK, p38 and ERK1/2 was strongly suppressed. Our data indicated that the anti-inflammatory effect of ERE in LPS-stimulated macrophages was partly mediated by its inhibition of JNK, p38 and ERK1/2.