The anti-inflammatory activity of avarol and avarone, sesquiterpenoid derivatives from the Mediterranean sponge Dysidea avara, was investigated. Both compounds potently inhibited paw oedema induced by carrageenan (approximated ED50 = 9.2 and 4.6 mg/kg, p.o., respectively) as well as ear oedema induced by 12-O-tetradecanoylphorbol acetate (TPA; ED50 = 97 and 397 micrograms/ear, respectively) in mice, with effects comparable to those of indomethacin. In A23187-stimulated rat peritoneal leukocytes, avarol showed an IC50 = 0.6 and 1.4 microM for inhibition of leukotriene B4 and thromboxane B2 release, respectively, with avarone showing a slightly lower potency. Both marine metabolites failed to show xanthine oxidase inhibitory activity or superoxide scavenging effects but were potent inhibitors of superoxide generation in rat peritoneal leukocytes activated by different stimuli, with an IC50 below the microM range. Only avarol was able to inhibit human recombinant synovial phospholipase A2 activity with an IC50 = 158 microM, and thus this compound showed a potency higher than that of mepacrine. Avarol and avarone effectively control acute inflammation in experimental models after either oral or topical administration and their anti-inflammatory activity may result from inhibition of eicosanoid release and depression of superoxide generation in leukocytes.