Accumulation of neutrophils in a random pattern skin flap has been demonstrated to contribute to the necrosis of distal flap tissue. This study proposes that administration of propofol anesthesia can effectively reduce neutrophil activity and enhance skin flap survival. The study was a randomized controlled trial using male Sprague-Dawley rats as subjects. For flap survival studies, a 3- by 12-cm, dorsal, cranial-based, random pattern skin flap was elevated and reapproximated. Flaps were examined for viability 10 days postsurgery. To assess neutrophil activity, flap biopsies were taken 12, 24, or 48 hours postsurgery from distal, middle, and proximal flap regions, and myeloperoxidase enzyme content was analyzed. Animals were randomly assigned to 1 of 4 groups: group 1, ketamine anesthesia (controls); group 2, propofol anesthesia; group 3, ketamine anesthesia plus 10% lipid emulsion (propofol vehicle); group 4, ketamine anesthesia without flap elevation (nonoperated controls for myeloperoxidase study). Flap survival was significantly improved in the propofol group compared with both the ketamine and vehicle control groups (P <0.01). Increased flap viability was correlated with a reduction in myeloperoxidase content in the propofol group compared with control operated animals, with minor variations observed in the different flap regions and time points tested. This study indicates that the use of propofol can potentially improve skin flap survival. The beneficial effects may be attributed to a reduction in neutrophil activity within the flap.