Following an ischemic episode, reperfusion causes profound oxidative stress in the vasculature of the afflicted tissue/organ. The dysregulated accumulation of reactive oxygen species (ROS), such as superoxide, has been closely linked to the production and release of pro-inflammatory mediators, a profound increase in adhesion molecule expression by the vascular endothelium and the infiltration of neutrophils during ischemia-reperfusion (I/R). Superoxide dismutase (SOD) has been shown to protect tissues and organs against I/R-induced injury however, either the drug had to be continuously perfused or kidneys had to be occluded to prevent clearance. In this study we used intravital microscopy, a system that allowed us to visualize neutrophil:endothelial interactions within the mesenteric postcapillary venules of cats subjected to I/R, and tested the hypothesis that I/R-induced neutrophil recruitment was inhibited by treatment with SOD2/3. SOD2/3 is a chimeric fusion gene product which contains the mature SOD2 as well as the C-terminal 'tail' of SOD3 and unlike the three naturally occurring SODs (SOD1-3) which bear a net negative charge at pH 7.4, SOD2/3 is positively-charged and physiologically stable. Our results suggest that not only does SOD2/3 have a much greater efficacy in vivo than the native human SOD2 but that it's administration prevents I/R-induced neutrophil:endothelial cell interactions and microvascular dysfunction. Moreover, our data support the hypothesis that reactive oxidants mediate I/R-induced injury and that the chimeric recombinant SOD2/3 has the potential to be a therapeutic agent against this debilitating illness.