The beneficial effects of alpha-difluoromethylornithine (DFMO) were assessed in a model of peripheral ischemia. DFMO is an irreversible inhibitor of ornithine decarboxylase (ODC), the initial enzyme in the production of polyamines. A 7 x 7 cm rat abdominal skin flap was surgically raised based on two inferior epigastric nerve, artery, and vein pedicles. One of the pedicles was then ligated and the skin was sutured back in place. Necrosis of skin was assessed 2 and 7 days after surgery. The rats were divided into four groups: control, DFMO, DFMO + polyamines, and polyamines alone. DFMO was administered in drinking water at 0.2%. Polyamines (putrescine, spermidine, and spermine) were each administered by daily i.p. injection at a dose of 10 mg/kg. The percentage of necrosis of the area of skin at risk in controls was 65 +/- 2% (mean +/- SEM). Necrosis was significantly reduced with DFMO (19 +/- 1%), with DFMO plus polyamines (37 +/- 3%), or with polyamines alone (41 +/- 2%). Protein synthesis and ornithine decarboxylase activity in the skin were both significantly decreased by DFMO. These studies demonstrate that DFMO protects skin from ischemic damage at least in part through actions on polyamine metabolism.