Antiflammins are synthetic peptides with sequence homology to proteins inhibitory for phospholipase A₂ (EC 3.1.1.4). The effect of antiflammin 2 on murine arachidonate or 12-O-tetra-decanoylphorbol 13-acetate (TPA)-induced ear oedema has been studied. Topical application of arachidonic acid (AA) produced a short-lived oedema response with rapid onset associated with marked increases in prostaglandin E₂ levels. TPA produced a longer-lasting oedema associated with marked influx of neutrophils and mononuclear cells as well as predominant formation of leukotriene B₄ (LTB₄). Topical pretreatment with indomethacin or dexamethasone reduced plasma leakage, oedema and prostaglandin E₂ biosynthesis in AA-induced oedema, whereas antiflammin 2 had no effect. However, topical pretreatment with antiflammin 2 dose-dependently reduced plasma leakage, cell influx, oedema and LTB₄ levels in response to TPA. These results indicate that the anti-inflammatory effect of antiflammins can be attributed to AA mobilization and/or 5 lipoxygenase inhibition but can be dissociated from an effect on arachidonic acid metabolism by the cyclooxygenase pathway.