Three "blood substitutes", a diaspirin cross-linked human hemoglobin (DBBF-Hb), a bovine polymerized hemoglobin (PolyHbBv), and a human polymerised hemoglobin (O-R-PolyHbA₀), that have undergone clinical trials, are used in this study. Previously we showed in the rat that co-administration of sodium selenite (Na₂SeO₃) and DBBF-Hb significantly decreased mesenteric venular leakage and epithelial disruption produced by DBBF-Hb alone, but did not reduce mast cell degranulation unless given orally. The purpose of this study was to determine whether Na₂SeO₃ produced similar beneficial responses when used with PolyHbBv and O-R-PolyHbA₀. In anesthetized Sprague-Dawley rats, the mesenteric microvasculature was perfused with PolyHbBv or O-R-PolyHbA₀, with and without Na₂SeO₃ in the perfusate and suffusate, for 10 min., followed by FITC-albumin for 3 min., and then fixed for microscopy. Sodium selenite did not significantly affect leak number or area, in preparations perfused with PolyHbBv, and only reduced leak number in preparations perfused with O-R-PolyHbA₀. Sodium selenite significantly increased mesenteric mast cell degranulation in both cases and impaired epithelial integrity in animals treated with PolyHbBv. In vitro, Na₂SeO₃ significantly reduced the oxidation rate of DBBF-Hb in the presence of oxidants, had little effect on PolyHbBv, and increased the oxidation rate of O-R-PolyHbA₀. These results suggest that Na₂SeO₃ moderates hemoglobin-induced damage, at least partly, through its redox interactions with the heme sites in the hemoglobin molecules, and that accessibility of the heme site to Na₂SeO₃ governs those interactions.