In sickle cell anemia (SCA), inflammatory events (intravascular sickling and transient vaso-occlusive events) result in chronic endothelium activation. In addition to sickling behavior, sickle (SS) red cells exhibit abnormal interaction with vascular endothelium that is considered to have an important role in the initiation of vaso-occlusion. Up-regulation of endothelial adhesion molecules caused by oxidants (and cytokines) may lead to increased SS red cell adhesion. We hypothesize that endothelial activation is indispensable in SS red cell adhesion to endothelium and that antioxidants will have an inhibitory effect on this interaction. To this end, we examined the effect of selected antioxidants in the ex vivo mesocecum vasculature, a well-established model that allows measurement of hemodynamic parameters and by intravital microscopy can quantify adhesion. We tested antioxidant enzymes (superoxide dismutase [SOD] and catalase) and an intravascular SOD mimetic polynitroxyl albumin (PNA) in the presence of platelet-activating factor (PAF); the latter causes endothelial oxidant generation and endothelial activation that characterize SCA. Importantly, in ex vivo preparations, PAF not only induced marked endothelial oxidant generation, but also enhanced SS red cell adhesion resulting in frequent blockage of small-diameter venules. The adhesion, inversely related to venular diameter, and vaso-occlusion were markedly inhibited by antioxidants, resulting in improved hemodynamics. In addition, PNA, the most effective antioxidant, also abolished SS red cell adhesion in preparations not activated by PAF. Thus, antioxidant therapy using a stable and long-acting molecule like PNA may have a potential in ameliorating SS red cell adhesion and related vaso-occlusion.