Tretinoin is currently marketed for topical treatment of acne vulgaris and has also been used in the rejuvenation of aging skin. After topical application, it has been shown to stimulate mitotic activity and increase vascularity in skin. In this study a porcine model was used to test the hypothesis that presurgical treatment with topical tretinoin would increase the surviving area of random full-thickness skin flaps. Four hybrid barrows, 40 to 60 lb, were treated with tretinoin and 4 similar animals were treated with placebo (carrier vehicle) for 2 weeks before raising four dorsally based full-thickness skin flaps (4 x 12 cm) on each animal. Biopsies were taken from tretinoin-treated, placebo-treated, and untreated skin at the time the flaps were initially raised and 1 week later before killing the animals. All tissue was processed for light and electron microscopy. One week after surgery, the pigs were killed. Photographs were taken at the termination of the experiment and the negatives were digitized and analyzed using a high-speed graphics workstation supported by SGITrace software. The percentage of skin flap survival was determined using this method of image analysis. Using repeated-measures analysis of variance, there was no significant difference in the mean flap survival between the tretinoin (mean = 46.75; SEM = 7.05) and placebo (mean = 65.80; SEM = 7.05) treated groups at the 0.05 significance level. Pretreatment with tretinoin did not enhance skin flap survival under the conditions of this study. Rationale for this finding and possible modifications of future studies are discussed.