Isoprostane E2 (8-iso PGE) and isoprostane F2 alpha (8-iso PGF) contribute to numerous vascular, proinflammatory, and nociceptive functions. The underlying mechanisms for many of their actions are still under investigation. We examined the ability of isoprostanes to promote cutaneous inflammation using the Evan's blue dye method. Our data show that 4 micrograms subcutaneously (s.c.) injected 8-iso PGE or 8-iso PGF induced plasma extravasation in glabrous rat skin. Dye extravasation was also elicited in hairy skin after injections of 8-iso PGE, but not after 8-iso PGF. Isoprostane-evoked dye extravasation can be reduced by pretreatment with both the S+ and R- isomers of the cyclooxygenase (COX)-inhibitor ibuprofen (30 mg/kg intraperitoneally), indicating perhaps a nonspecific inhibition; pretreatment with ketorolac (1 and 10 mg/kg i.v.) was without effect. Unlike isoprostane-induced cutaneous nociceptor sensitization, which is blocked in a stereospecific and dose-dependent manner by COX-inhibitors, the effect of these drugs on isoprostane-induced cutaneous plasma extravasation is less consistent. We conclude that at least a large component of the isoprostane effect on cutaneous plasma extravasation is COX-independent.