Ginsenoside Rc, one of major Ginsenosides from Panax ginseng, enhances γ-aminobutyric acid (GABA) receptor _A (GABA _A )-mediated ion channel currents. Ginsenoside Rc enhances GABA-mediated ion currents in oocytes expressing the GABA _A receptor. Ginsenoside Rc significantly inhibits the expression of macrophage-derived cytokines, such as TNF-α and IL-1β. Ginsenoside Rc also markedly suppresses the activation of TANK-binding kinase 1/IκB kinase ε/interferon regulatory factor-3 and p38/ATF-2 signaling in activated RAW264.7 macrophages, human synovial cells, and HEK293 cells. Ginsenoside Rc exerts its anti-inflammatory actions by suppressing TANK-binding kinase 1/IκB kinase ε/interferon regulatory factor-3 and p38/ATF-2 signaling. Ginsenoside Rc suppresses the nuclear translocation of phospho-ATF-2 and phospho-FRA-1, whereas the translocation of p65 at its peak time points (30 and 60 min) is not decreased by Ginsenoside Rc treatment. Ginsenoside Rc regulates the expression of the proinflammatory cytokine TNF-α, which is produced by macrophages, by suppressing AP-1 activation.