Neutrophil depletion has a beneficial effect on ischemic myocardium and skeletal muscle upon reperfusion. Antineoplastic agents reduce blood neutrophils effectively, and lead to neutrophil depletion. The purpose of this study was to investigate the effects of four antineoplastic agents in low doses (cyclophosphamide, cisplatinum, mitomycin-C, and 5-fluorouracil) on ischemia-reperfusion injury, using an epigastric island skin-flap model in rats. Fifty male Sprague-Dawley rats, weighing 250-300 g, were randomly divided into five groups, each consisting of 10 rats: control, cyclophosphamide, cisplatinum, mitomycin-C, and 5-fluorouracil groups. Epigastric island skin flaps (measuring 3.5 x 4 cm) were raised and subjected to 10 h of in situ ischemia, followed by 7-day reperfusion and evaluation. Treatment with antineoplastic agents (cyclophosphamide, cisplatinum, mitomycin-C, and 5-fluorouracil) was used to introduce neutropenia. Complete blood counts, cutaneous bleeding time, and skin-flap survival were evaluated. Additionally, levels of malonyldialdehyde (MDA), nitric oxide (NO), glutathione (GSH), glutathione peroxidase (GSH-Px), and superoxide dismutase (SOD) were measured from extracted skin tissue. Numbers of leukocytes and platelets were decreased in all experimental groups. However, neutropenia and thrombocytopenia were not seen. Cutaneous bleeding activity was prolonged in all experimental groups, but not above the normal value. MDA and NO levels were found to be lower in all four antineoplastic agent groups than in the control group, while GSH, GSH-Px, and SOD enzyme activities were significantly higher (P < 0.05). However, MDA and NO levels were significantly decreased in the cyclophosphamide and 5-fluorouracil groups, as compared to the cisplatinum and mitomycin-C groups (P < 0.01). Also, GSH, GSH-Px, and SOD enzyme activities were significantly increased in the cyclophosphamide and 5-fluorouracil groups, compared to the other two antineoplastic agent groups (P < 0.01). We conclude that antineoplastic agents have beneficial effects on ischemia-reperfusion injuries when their doses are carefully adjusted, by decreasing the number of leukocytes and platelets, and altering the activity of free oxygen radicals.