Background: The purpose of this study was to evaluate the effects of fondaparinux, a selective antithrombin III agonist, in comparison to the low-molecular-weight heparin enoxaparin in the survival of a congested skin flap. Materials and Methods: Eighteen axial-pattern auricular flaps were performed on rabbits using a well-described congested flap model. Animals were randomized into 2 treatment groups, enoxaparin (n = 6) and fondaparinux (n = 6), and a control group (n = 6) that received no treatment. Skin flap survival area was measured postoperatively at 7 and 14 days. Results: The groups that received fondaparinux and enoxaparin had similar mean flap survival areas and were not statistically different. However, both treatment groups significantly increased flap survival compared with controls (P < 0.014). Conclusions: Fondaparinux, like enoxaparin, significantly improves survival of congested flaps in rabbits. Its use instead of enoxaparin may be warranted, given that it eliminates the risk of heparin-induced thrombocytopenia. Further study in humans is warranted.