BACKGROUND: The effects of perfluorocarbon (PFC) emulsions administered at a nonhemodiluting dose were studied in the hamster window chamber model to determine the difference in ischemia-reperfusion injury associated with PFC delivery before and after an ischemic episode. STUDY DESIGN: Ischemia was induced by compressing the periphery of the window chamber for 1 hour. Vessel diameter, red blood cell velocity, rolling and adherent leukocytes, and functional capillary density (FCD) were assessed by intravital. microscopy. The animals received an infusion (10% blood volume) of PFC emulsion or equivalent volumes of saline, before or after ischemia. Two groups were studied in each experimental protocol: A, infusion after ischemia; and B, infusion before ischemia, where a fraction of the infused material stagnated in the ischemic zone during the occlusion time. Measurements were made before induced ischemia and at 0.5, 2, and 24 hours of reperfusion. RESULTS: Animals treated with PFC after ischemia had substantially decreased leukocytes rolling and sticking in postcapillary venules and recovered functional capillary density and blood flow when compared with saline-treated controls. Conversely, administration of PFC before ischemia considerably reduced functional capillary density and increased leukocyte activation after reperfusion. CONCLUSIONS: Results indicate that PFC without stagnation within an ischemic zone attenuates postischemic reperfusion injury of striated skin muscle, presumably through the reduction of leukocyte-endothelial cell interactions. Accordingly, PFC effects on ischemia-reperfusion injury are determined mainly by the time of administration relative to the ischemic episodes.