Erythropoietin (EPO) is a type I cytokine that utilizes different receptor isoforms either to maintain hematopoiesis or protect against injuries that arise from widely diverse etiologies. EPO also facilitates healing by reducing inflammation and mobilizing endothelial progenitor cells to participate in restorative neoangiogenesis, but it is unclear which EPO receptor isoform is responsible for healing and whether this receptor use varies according to the type of wound. In the present studies carried out in the rat, we have utilized receptor-selective derivatives of EPO to determine which receptor type operates in (i) a nonischemic wound (skin punch biopsy), (ii) a permanently ischemic wound (raised musculocutaneous flap), (iii) an intermittent ischemic reperfusion wound (pressure or decubitus ulcer), or (iv) wounds complicated by infection (cecal ligation and perforation). Using these models, we demonstrate that nonerythropoietic tissue protective compounds administered immediately following injury limit wound size and accelerate eschar closure independent of wound type. Moreover, in a model of peritonitis-induced adhesions, daily administration of the nonerythropoietic derivative carbamyl-EPO (10 microg/kg-bw) was associated with significantly lower serum TNFalpha concentration, illness scores, increased survival, as well as decreased adhesion formation. These results confirm that wound healing is mediated by the tissue protective receptor isoform and argue that nonerythropoietic tissue protective molecules constitute promising new.