5-Oxo-eicosatetraenoate (5-oxoETE), a newly defined arachidonate metabolite, resembled 5-hydroxyeicosatetraenoate (5-HETE) in stimulating neutrophils to mobilize Ca2+ an in promoting PMN degranulation responses to other agents. It was, however, 10-fold stronger than 5-HETE and, like leukotriene (LT) B4, had intrinsic PMN degranulating effects. Nonetheless, 5-oxoETE and 5-HETE desensitized PMN to themselves or each other but not to LTB4; LTB4 desensitized to itself but not to 5-oxoETE or 5-HETE; and an antagonist blocked LTB4 but not 5-oxoETE or 5-HETE. 5-OxoETE and 5-HETE thus induce diverse PMN responses using a shared, down-regulatable, and receptor-like mechanism that does not involve LTB4 receptors; 5-oxoETE is the preferred natural agonist for this mechanism.