OBJECTIVE: To determine the efficacy of topical anti-ischemic drug therapy in the salvage of failing, random-pattern skin flaps. DESIGN: Prospective, randomized, placebo-controlled, therapeutic trial. SETTING: Academic medical center. SUBJECTS: Sixty-one adult male Sprague-Dawley rats. INTERVENTION: Each experimental rat underwent a caudally based random-pattern skin flap using the modified McFarlane technique. Rats were randomized to 1 of 6 treatment groups: topical nifedipine, topical trolamine salicylate, topical nitroglycerin, topical trolamine salicylate-nitroglycerin combination, topical nifedipine-trolamine salicylate-nitroglycerin combination, or inert carrier ointment (control). Treatment was initiated immediately following flap closure and continued every 6 hours for 7 days. At the end of the treatment period, animals were euthanized and flap survival was determined for each one. RESULTS: Topical anti-ischemic drug therapy resulted in a statistically significant reduction in ischemic flap necrosis for each drug (or combination) tested relative to the 44.2% mean necrosis observed in control animals. Treatment with the combination of topical nitroglycerin and topical trolamine salicylate resulted in the best salvage response (25.2% mean necrosis) with a statistically significant improvement in flap survival relative to both controls and nitroglycerin alone. CONCLUSIONS: Topical anti-ischemic agents are effective in reducing ischemic necrosis of failing, random-pattern skin flaps in the rat model. Although nitroglycerin, trolamine salicylate, and nifedipine possess unique pharmacologic mechanisms of action, each drug produced a statistically significant improvement in flap survival. The results of this study suggest that topical drug therapy may play an important role in clinical salvage of the failing skin flap. Further studies are needed to explore the potential of combination drug therapy.