Leaves or infusions of feverfew, Tanacetum parthenium, have long been used as a folk remedy for fever, arthritis and migraine, and derived products are widely available in U.K. health food shops. Previous reports have suggested interactions with arachidonate metabolism. Crude chloroform extracts of fresh feverfew leaves (rich in sesquiterpene lactones) and of commercially available powdered leaves (lactone-free) produced dose-dependent inhibition of the generation of thromboxane B2 (TXB2) and leukotriene B4 (LTB4) by ionophore- and chemoattractant-stimulated rat peritoneal leukocytes and human polymorphonuclear leukocytes. Approximate IC50 values were in the range 5-50 micrograms/mL, and inhibition of TXB2 and LTB4 occurred in parallel. Isolated lactones (parthenolide, epoxyartemorin) treated with cysteine (to neutralize reactive alpha-methylene butyrolactone functions of the sesquiterpenes). Inhibition of eicosanoid generation appeared to be irreversible but not time-dependent. We conclude that feverfew contains a complex mixture of sesquiterpene lactone and non-sesquiterpene lactone inhibitors of eicosanoid synthesis of high potency, and that these biochemical actions may be relevant to the claimed therapeutic actions of the herb.