Erythropoietin (EPO) has been proposed as a novel cytoprotectant in ischemia/reperfusion (I/R) of the brain, heart and kidney. There is no information, however, whether EPO exerts its protection by prevention of postischemic microcirculatory deteriorations. Here, we investi-gated the effect of EPO on I/R-induced microcirculatory dysfunctions. Using the mouse dor-sal skinfold chamber preparation, nutritive microcirculation and leukocyte-endothelial cell interaction were studied in striated muscle by in vivo fluorescence microscopy before 3h ischemia and during 5 days reperfusion. Animals were pretreated with EPO (5000U/kg body weight) 1h or 24h before ischemia. Vehicle-treated I/R animals served as controls. Additional animals underwent sham operation only or received EPO pretreatment without I/R. I/R pro-voked a significant (p<0.05) reduction of functional capillary density, an increase of mi-crovascular permeability, and an enhancement of venular leukocyte-endothelial cell interac-tion during early reperfusion. This was associated with a pronounced (p<0.05) arteriolar con-striction and diminution of blood flow during late reperfusion. Pretreatment with EPO in-duced EPO-receptor and eNOS expression at 6h of reperfusion (p<0.05). In parallel, EPO significantly (p<0.05) reduced capillary perfusion failure and microvascular hyperpermeabil-ity during early reperfusion, and arteriolar constriction and flow reduction during the later reperfusion phase. EPO pretreatment further substantially (p<0.05) diminished I/R-induced leukocytic inflammation by reducing the number of rolling and firmly adhering leukocytes in postcapillary venules. Of interest, EPO, in particular if applied 1h before ischemia, addition-ally induced angiogenic budding and sprouting at day 1 and 3, and formation of new capillary networks at day 5 of reperfusion. Thus, our study demonstrates for the first time that EPO effectively attenuates I/R injury by preserving nutritive perfusion, reducing leukocytic in-flammation and inducing new vessel formation.