The effect of 21-aminosteroid, a lazaroid (U74389F), on tissue injury after secondary ischemia was evaluated in 3 x 5 cm island skin flaps in male Sprague-Dawley rats (n = 30). Primary ischemia was produced by arteriovenous occlusion for 1 hour. Eighteen hours later, secondary ischemia was inflicted by 4-hour venous occlusion. The treatment group received intravenous lazaroid (3 mg/kg) 30 minutes before the start of secondary ischemia. The control group received the same volume of citrate buffer vehicle using the same route and schedule. Skin-flap survival was an all-or-none phenomenon and assessed at 7 days after secondary ischemia. Malondialdehyde (MDA) content was measured to determine the occurrence of lipid peroxidation. Myeloperoxidase (MPO) activity was assayed to assess the degree of neutrophil infiltration. Treatment with this lazaroid significantly improved the survival rate from 0 percent (0 of 13) to 53 percent (9 of 17) (p < 0.01). Malondialdehyde content was 62 +/- 10 (mean +/- SEM, n = 4) pmol/mg dry weight in normal skin. Malondialdehyde increased by 3 times normal in the flaps destined to survive and by 13 times in the flaps destined to undergo necrosis (p < 0.001). Myeloperoxidase activity was negligible in normal skin. At the end of secondary ischemia, the flaps destined to survive exhibited a high myeloperoxidase activity. The flaps destined to necrosis showed the enzyme activity 2.2 times more than surviving flaps (p < 0.01). The results suggest that the lazaroid U74389F may improve survival by attenuating neutrophil infiltration and by reducing lipid peroxidation.