Despite continued improvements in surgical technique and postoperative management of pedicled flaps, partial flap necrosis continues to be a substantial problem. Several researchers sought interventions that would decrease the incidence of this complication. The hypothesis of this study is that a bovine hemoglobin-based, oxygen-carrying solution (HBOC-201) will increase oxygen delivery, thus decreasing the area of necrosis of the marginally perfused portions of a pedicled flap. Eighty male Sprague-Dawley rats were randomly assigned to one of four groups (20 animals in each group): group 1, controls (surgical creation of flap only); group 2, HBOC-201, 2 g i.v., administered preoperatively and on days 3 and 5; group 3, HBOC-201, 4 g i.v., administered preoperatively and on days 3 and 5; and group 4, hemodilution (lactated Ringer's solution) administered preoperatively and on days 3 and 5. A ventral fasciocutaneous flap (5 × 7 cm) was elevated, based on unilateral superficial inferior epigastric vessels, and the flap was replaced and sutured. Animals were examined daily and euthanized on day 7. Prior to euthanasia, digital photographs were taken of each subject, and the images were analyzed for total area of the flap and area of necrosis, using ImagePro® software. Using the calculated percentage of necrosis for each animal, a mean value of percent necrosis was obtained for each animal group and used for statistical analysis. Animals in group 2 demonstrated a decreased area of necrosis when compared with the control group (9.14% vs. 22.24%, P = 0.014). In conclusion, the oxygen therapeutic HBOC-201, at a dose of 2 g, administered preoperatively and on days 3 and 5, decreased the area of necrosis in a rat model of epigastric skin-flap failure. Further investigation of this drug and its effects on flap survival is warranted. © 2006 Wiley-Liss, Inc.