The role of the sialyl Lewisx(sLex)-decorated version of soluble complement receptor type 1 (sCR1) in moderating skeletal muscle reperfusion injury, by antagonizing neutrophil endothelial selectin interaction and complement activation, is examined. Mice underwent 2 h of hindlimb ischemia and 3 h of reperfusion. Permeability index (PI) was assessed by extravasation of125I-labeled albumin. Neutrophil depletion and complement inhibition with sCR1 reduced permeability by 72% (PI 0.81 ± 0.10) compared with a 42% decrease (PI 1.53 ± 0.08) observed in neutropenic mice, indicating that part of the complement-mediated injury is neutrophil independent. sCR1sLextreatment reduced PI by 70% (PI 0.86 ± 0.06), an additional 20% decrease compared with sCR1 treatment (PI 1.32 ± 0.08). Treatment with sCR1sLex0.5 and 1 h after reperfusion reduced permeability by 63% (PI 0.09 ± 0.07) and 52% (PI 1.24 ± 0.09), respectively, compared with the respective decreases of 41% (PI 1.41 ± 0.10) and 32% (PI 1.61 ± 0.07) after sCR1 treatment. Muscle immunohistochemistry stained for sCR1 only on the vascular endothelium of sCR1sLex-treated mice. In conclusion, sCR1sLexis more effective than sCR1 in moderating skeletal muscle reperfusion injury.