<i>Objective:</i> Erythropoietin (EPO) has cytoprotective effects apart from its hematopoietic effects. We studied the effects of different EPO molecules on podocyte signaling in vitro and on podocyte survival in an experimental model of diabetic kidney injury (db/db mouse). <i>Methods:</i> We elucidated intracellular signaling by epoetin-β, darbepoetin-α, and the continuous erythropoietin receptor activator (CERA) in immortalized murine podocyte cultures. Moreover, we treated db/db micewith placebo or with CERA in a chronic (14-week) randomized controlled study. We also studied non-diabetic db/m mice as controls. <i>Results:</i> We could clearly demonstrate phosphorylation of the JAK/PI3K pathway and Akt signaling in podocytes by epoetin-β, darbepoetin-α and CERA. In the long-term animal study we found significantly reduced podocyte numbers in placebo-treated db/db mice compared to db/m control mice (7.4 ± 0.2 vs. 10.2 ± 0.9 per glomerular field; p < 0.05). Chronic CERA treatment ameliorated podocyte loss in kidneys of diabetic animals (8.5 ± 0.5 per glomerular field; p < 0.05 vs. placebo-treated db/db mice). <i>Conclusion:</i> EPO activates pro-survival intracellular pathways in podocytes in vitro, and ameliorates diabetes-induced podocyte loss in vivo. Chronic EPO administration may be a feasible way to protect podocyte from diabetic injury.