Objective: Neutrophils (PMNs) contribute importantly to the tissue injury associated with ischemia and subsequent reperfusion of a vascular bed. The effects of a recombinant soluble human form of P-selectin glycoprotein ligand-1 (rsPSGL.Ig) on PMN–endothelial cell interactions were investigated in a well established model of feline myocardial-ischemia reperfusion injury. Methods: Cats were subjected to 90 min of myocardial ischemia followed by 270 min of reperfusion. Results: Administration of rsPSGL.Ig (1 mg/kg) just prior to reperfusion resulted in a significant reduction in myocardial necrosis compared to that in cats administered a low affinity mutant form of rsPSGL.Ig (1 mg/kg) (16±3 vs. 42±7% of area-at-risk, P<0.01). Cardioprotective effects were confirmed by significant (P<0.05) reductions in plasma creatine kinase activity in cats treated with rsPSGL.Ig. Inhibition of PMN–endothelial cell interactions was evidenced by a significant attenuation in cardiac myeloperoxidase activity (P<0.01) and reduced PMN adherence to ischemic–reperfused coronary endothelium (P<0.001). In addition, rsPSGL.Ig treatment significantly (P<0.01) preserved endothelium-dependent vasorelaxation in ischemic–reperfused coronary arteries. Conclusion: These results demonstrate that the administration of a recombinant soluble PSGL-1 reduces myocardial reperfusion injury and preserves vascular endothelial function, which is largely the result of reduced PMN–endothelial cell interactions.