OBJECTIVE To determine whether treatment with the combination of hyperbaric oxygen and free-radical scavengers or inhibitors would result in increased skin-flap survival. METHODS An animal model with male Sprague-Dawley rats was used. The flap was a cranial-based dorsal 3 x 12-cm random-pattern skin flap that included the panniculus carnosus. Rats were randomly assigned to one of 10 treatment groups. METHODS The radical scavengers superoxide dismutase, catalase, and alpha-tocopherol acetate and the inhibitor allopurinol were used to combat or scavenge radicals. Oxygen (100%) treatments were for 90 minutes at 2.5 atm absolute daily. METHODS At 7 days, the flaps were examined for survival by fluorescein injection. Lipid peroxidation as a measure of tissue damage was measured by thiobarbituric acid-malondialdehyde analysis. RESULTS The combination of treatments resulted in significantly increased flap survival compared with untreated controls (P < .05) except in the group treated with allopurinol and hyperbaric oxygen. Lipid peroxidation was inhibited by the superoxide dismutase plus catalase and the alpha-tocopherol treatments but not by treatment with allopurinol. CONCLUSIONS Moderate doses of radical scavengers or antioxidants coupled with a conservative hyperoxic exposure regimen can result in the increased survival of random-pattern skin flaps.