We previously reported that erythropoietin inhibits renal and vascular dysfunction by activating PI3K/Akt pathway in animal models such as type 1 diabetes. The PI3K/Akt pathway is the central components in insulin signaling. Impairment of insulin signaling occurs not only in hepatic and muscle cells but also in vascular and renal cells, which are suggested to contribute to tissue injury. We investigated whether erythropoietin would inhibit glucose tolerance and vascular and renal injury. Rats were treated with 12%sucrose in drinking water and erythropoietin (150U/kg, 3 times/week) subcutaneously for 10 weeks. Despite our previous results, erythropoietin (150U/kg) induced hematopoiesis and hypertension. Maybe because of hypertension, impairment of endothelium-dependent vasodilation, medial thickening and proteinuria in insulin resistant rats were worsened by erythropoietin. While reducing the dose (75U/kg) and period (last 4 weeks of sucrose treatment) even caused mild hypertension, erythropoietin had no effects on endothelial function, medial thickness, or proteinuria. Oral glucose tolerance test and the value of HOMA-IR showed that erythropoietin improved insulin sensitivity. Erythropoietin reduced fibrotic collagen deposition in renal tubulointerstitial area and macrophage infiltration in aortic adventitia. In conclusion, erythropoietin might protect vascular and renal injury in insulin resistant state. Further investigation into insulin signaling and modification of treatment dose/period are needed.