Local hypoxia, as due to trauma, surgery or arterial occlusive disease, may severely jeopardize the survival of the affected tissue and its wound healing capacity. Initially developed to replace blood transfusions, artificial oxygen carriers have emerged as oxygen therapeutics in such conditions. The aim of this study was to target primary wound healing and survival in critically ischemic skin by systemic application of left-shifted liposomal hemoglobin vesicles (HbVs). This was tested in bilateral, cranially based dorsal skin flaps in mice treated with a HbV solution with an oxygen affinity that was increased to a P₅₀ of 9 mmHg. Twenty percent of total blood volume of HbV solution were injected immediately and 24 h after surgery. On the first postoperative day, oxygen saturation in the critically ischemic middle flap portions was increased from 23 % (untreated control) to 39 % in the HbV-treated animals (P < 0.05). Six days postoperatively, flap tissue survival was increased from 33% (control) to 57% (P < 0.01) and primary healing of the ischemic wound margins from 6.6 mm to 12.7 mm (P < 0.05) after HbV injection. In addition, higher capillary counts and endothelial nitric oxide synthase (eNOS) expression (both P < 0.01) were found in the immunostained flap tissue. We conclude that left-shifted HbVs may ameliorate the survival and primary wound healing in critically ischemic skin, possibly mediated by eNOS-induced neovascularization.