Etodolac (Ultradol) is a new tetrahydropyrano-indole derivative which has shown pronounced analgesic and antiinflammatory properties. Its effects on the different pathways of metabolism of arachidonic acid have been studied and compared to the effects of indomethacin and benoxaprofen. All three drugs tested inhibited the cyclooxygenase activity of the parenchyma as assessed by inhibition of LTB4- and LTD4-induced contraction. However, the activity of human polymorphonuclear leukocyte 5-lipoxygenase and of human platelet 12-lipoxygenase was inhibited only by very high concentrations (1 X 10(-4) M and over) of these compounds, whereas nordihydroguaiaretic acid (NDGA) was active at concentrations 100 times lower. In the Schultz-Dale reaction of the guinea pig trachea, etodolac, benoxaprofen, and indomethacin produced increases of the myotropic contractile activity of the tissues sensitized to ovalbumin. Our results do not lend support to the hypothesis that the mechanism of action of these antiinflammatory drugs is linked to the inhibition of lipoxygenases.