Septic shock is the most common cause of death in intensive care units, and no effective treatment is available at present. Lipopolysaccharide (LPS) is the primary mediator of Gramnegative sepsis by inducing the production of macrophagederived proinflammatory cytokines, in which activation of nuclear factor-kB (NF-kB) plays an important role. PC-SPES is an eight-herb mixture active against a variety of malignancies, including prostate cancer and leukemia. In this study, we demonstrated that PC-SPES inhibited the LPS-induced NF-kB reporter activity in RAW264.7 macrophages. Electrophoretic mobility shift assay showed that PC-SPES inhibited the binding of NF-kB to specific DNA sequences; however, it did not affect either degradation of inhibitory kBα or nuclear translocation of NF-kB. Also, we explored the effect of PCSPES on LPS-induced mitogen-activated protein (MAP) kinase signaling; PC-SPES did not affect LPS-induced phosphorylation of MAP kinases, including c-Jun NH2-terminal kinase, p38, and extracellular signal-regulated kinase 1/2. Moreover, PC-SPES decreased the production of proinflammatory cytokines and inducible enzymes, such as tumor necrosis factor (TNF) α, interleukin (IL)-1β, IL-6, cyclooxy-genase-2, as well as inducible nitric-oxide synthase in RAW264.7 macrophages and peritoneal macrophages from C57BL/6 mice after the cells were stimulated by either LPS or LPS and interferon-γ. Furthermore, PC-SPES rescued C57BL/6 mice from death caused by LPS-induced septic shock in conjunction with decreased serum levels of TNFα and IL-1β. Together, PC-SPES is a potent inhibitor of NF-kB and might be useful for the treatment of sepsis and inflammatory diseases.