Infiltrating polymorphonuclear leukocytes (PMNs) have been implicated as key mediators of ischemia/reperfusion injury of the heart. These toxic effects are due to PMN and endothelial cell interactions. This microvascular dysfunction results in an impairment of the coronary circulation which enhances myocardial damage. The effect of defibrotide was examined in a neutrophil dependent isolated perfused rat heart model of ischemia (I) (20 min) and reperfusion (R) (45 min). Administration of defibrotide (200 micrograms/kg) to I/R hearts in the presence of PMNs preserved coronary flow and protected against cardiac contractile dysfunction (p < 0.001) in comparison to those I/R hearts perfused with PMNs but receiving only vehicle. Defibrotide also significantly decreased PMN accumulation in the ischemic myocardium as evidenced by an attenuation in myeloperoxidase activity (p < 0.001). Defibrotide exerted a significant cardioprotection in PMN mediated I/R injury of rat heart. The mechanism appears to be related to inhibition of PMN-endothelium interaction and eventual PMN infiltration into the ischemic myocardium.