The efficacy of preventing ischemia-reperfusion damage by employing native or modified (mPEG-SOD) superoxide dismutase in an experimental animal model of acute ischemia of the left hindlimb was tested. Four hours and thirty minutes complete warm ischemia was induced in the left hindlimb of 43 Wistar rats, by clamping the femoral artery and monitoring its efficacy with Laser Doppler flowmetry. After ten days, a significative difference (p = 0.004) of the survival leg rate was found in the group treated with mPEG-SOD (86.6%) compared with the control group (30%). Histomorphological and ultrastructural analysis were performed at different time intervals confirming what the clinical course had already pointed out. These results show that SOD in its modified form, despite the lower dosage, can provide good protection against ischemia/reperfusion injury of muscles.