An altered metabolism of endothelial cell-derived nitric oxide has been implicated in the microvascular dysfunction associated with ischemia/reperfusion. The objective of this study was to examine whether S-nitroso human serum albumin, a novel nitric oxide-donor, improves flap viability and whether it influences edema formation after prolonged ischemia when administered prior to and in the initial phase of reperfusion. Denervated epigastric island skin flaps were elevated in 30 male Sprague Dawley rats, rendered ischemic for 8 hours, subsequently reperfused and further observed for either 3 hours (acute) or 7 days (chronic). In the sham rats (n = 6), skin flaps were elevated only. Starting 1 hour prior to reperfusion, S-nitroso human serum albumin (n = 12) or human serum albumin (n = 12) as placebo was infused systemically for 2 hours. In the chronic model, flap necrosis as well as viable flap size was evaluated after 7 days of reperfusion in six rats per group, comparing to sham rats. In the acute model, edema formation was evaluated after 3 hours of reperfusion in six rats per group. Administration of S-nitroso human serum albumin significantly decreased flap necrosis from 18.1 +/- 15.6% in the human serum albumin group to 2.1 +/- 1.5% in the S-nitroso human serum albumin group, which was similar to the sham group (2.5 +/- 4.2%). Viable flap size (sham 13.4 +/- 1.6 cm2) was also significantly improved in the S-nitroso human serum albumin group (10.1 +/- 1 cm2) versus the human serum albumin group (7.0 +/- 2.2 cm2). There was no significant difference between the groups regarding postischemic edema formation. These results show that administration of S-nitroso human serum albumin prior to and in the initial phase of reperfusion significantly improves flap viability after 7 days but does not influence early observable edema formation. These findings support the role of nitric oxide as an important mediator in the protection against skin flap ischemia/reperfusion injury.