The objective of this study was to determine whether platelet-activating factor (PAF) mediates the leukocyte-endothelial cell interactions elicited by ischemia/reperfusion. The rates of adherence and extravasation of leukocytes were monitored in cat mesenteric venules subjected to 60 min of ischemia (blood flow reduced to 20% of control) followed by 60 min of reperfusion. Leukocyte rolling velocity, red blood cell velocity, and vessel diameter were also measured. The experiments were performed in control (untreated) animals and in animals pretreated with one of two PAF receptor antagonists, i.e., BN 52021 or WEB 2086. The responses of venular blood flow, wall shear rate, and vessel diameter did not differ between the three groups. In the control group, 1 h of ischemia was associated with significant adherence and extravasation of leukocytes, with reperfusion greatly enhancing these responses. The rates of leukocyte adherence and extravasation during reperfusion were greatly attenuated by both PAF antagonists. Furthermore, the proportion of adherent leukocytes that ultimately extravasate during reperfusion was markedly reduced by WEB 2086. These results suggest that PAF plays an important role in mediating the adhesive interaction between circulating leukocytes and microvascular endothelium induced by ischemia/reperfusion and that the phospholipid promotes the leukocyte extravasation associated with ischemia/reperfusion.