Progression of inflammatory processes correlates with the release of cell-derived mediators from the local site of inflammation. These mediators, including cytokines of the IL-1 and IL-6 families, act on host cells and exert their action by activating their signal transduction pathways leading to specific target gene activation. Parthenolide, a sesquiterpene lactone found in many medical plants, is an inhibitor of IL-1-type cytokine signaling that blocks the activation of NF-kappa B, Here we show that parthenolide is also an effective inhibitor of IL-6-type cytokines. It inhibits IL-6-type cytokine-induced gene expression by blocking STAT3 phosphorylation on Tyr705. This prevents STAT3 dimerization necessary for its nuclear translocation and consequently STAT3-dependent gene expression. This is a new molecular mechanism of parthenolide action that additionally explains its anti-inflammatory activities.