Secondary venous ischemia caused by anastomotic failure is one of the major causes of failure after free tissue transfers and replantations. The effects of cyclosporin A (CsA) on secondary ischemic injury associated with neutrophil infiltration and lipid peroxidation were evaluated in a rat inferior epigastric island skin flap model. Primary ischemia was produced by arteriovenous occlusion for 2 hours. Twenty-four hours later, secondary venous ischemia was produced by 5 hours of venous occlusion. Nonischemic (n = 5), primary ischemic (n = 5), and secondary ischemic control groups (n = 10), and four treatment groups (n = 10) were created. Treatment groups received either 15 or 30 mg per kilogram per day oral CsA for 3 days before flap elevation, or 15 or 30 mg per kilogram intravenous CsA at 4 hours of secondary venous ischemia. Flap survival area, malondialdehyde (MDA) content, and myeloperoxidase (MPO) activity were assayed for each group. The mean flap survival area of the high-dose posttreatment group was significantly higher than the secondary ischemic control group (29% +/- 39% vs. 3% +/- 8%; p < 0.05, Student's t-test). The MDA and MPO levels of each treatment group were significantly lower than the secondary ischemic control group at hours 1 and 24 (p < 0.0001, Student's t-test). The lowest MDA and MPO levels were achieved in the high-dose posttreatment group. Results suggest that CsA may improve flap survival after secondary venous ischemia by attenuating neutrophil infiltration and by reducing lipid peroxidation.