Echinacea plant preparations are widely used in the prevention and treatment of common cold. However, so far no molecular mechanism of action has been proposed. We analyzed the standardized tincture Echinaforce TM and found that it induced de novo synthesis of tumor necrosis factor a (TNF-a) mRNA in primary human monocytes/macrophages, but not TNF-a protein. Moreover, LPS-stimulated TNF-a protein was potently inhibited in the early phase but prolonged in the late phase. A study of the main constituents of the extract showed that the alkylamides dodeca-2E,4E,8Z,10E/Z-tetraenoic acid isobutylamides (1/2), trienoic (3) and dienoic acid (4) derivatives are responsible for this effect. The upregulation of TNF-a mRNA was found to be mediated by CB2 receptors, increased cAMP, p38/MAPK and JNK signaling, as well as NF-jB and ATF-2/CREB-1 activation. This study is the first to report a possible molecular mechanism of action of Echinacea, highlighting the role of alkylamides as potent immunomodulators and potential ligands for CB2 receptors.