During reperfusion of skeletal muscle after ischemia, lipid mediators, mainly eicosanoids, are released and may have a role in the pathogenesis of reperfusion injury. To validate the role of eicosanoids in the ischemia-reperfusion induced functional deficits in skeletal muscle, we compared muscle edema and the changes of eicosanoid concentration in the rat hind limb after ischemia-reperfusion injury by application of tourniquet. After 4 hours of ischemia, reperfusion was established for 4 hours by releasing tourniquet. To assess tissue damage, edema, and wet/dry weight ratios were determined and the eicosanoid concnentrations were measured by the HPLC. The muscle edema and the release of cyclooxygenase metabolites were not induced by the ischemia itself rather they were significantly increased by reperfusion. Indomethacin treatment ameliorated limb edema and decreased the release of 6-keto-PGF1α, thromboxane B2, and PGE2 induced by reperfusion. But the inhibitory effect of indomethacin on edema (35%) was relatively low than the inhibitory effect on release of cyclooxygenase metabolites (up to 69%) by reperfusion. These results support the view that cyclooxygenase products may play a significant role in the formation of muscle injury by ischemia-reperfusion and suggest that nonsteroidal antiinflammatory agents might be partially beneficial to the management of acute limb ischemia-reperfusion injury.