Elevation of rat abdominal skin flaps, followed by ligation and division of the left inferior neurovascular pedicle, resulted in only a 40% survival of the area normally perfused by the ligated artery and vein. Superoxide dismutase (SOD) (EC 1.15.1.1) administered i.v. (20,000 U/kg) 30 min before flap elevation increased survival to 52%. SOD derivatized with polyethylene glycol, which increases circulating half-life, was more effective, increasing survival to 80%. This protective effect resulted from the catalytic activity of the derivatized enzyme because inactivation by treatment with H2O2 eliminated its effect on skin flap survival. An equimolar mixture of Desferal and MnCl2, which catalyzes the dismutation of O2- in vitro, improved survival to 72%. Desferal-Fe3+, which lacks in vitro SOD activity, or Mn2+ alone did not affect the survival of skin flaps, but Desferal alone was nearly as effective as the Desferal-Mn2+ mixture. This effect of Desferal may result from acquisition of and subsequent removal of iron in vivo. These results support the view that the superoxide radical or a product derived from it plays a role in limiting the survival of island skin flaps.