Neuroprotective functions of erythropoietin (Epo) are thought to involve a heteroreceptor composed of both Epo receptor (Epo-R) and common beta chain (betac). Here, we measured the response of hippocampal Epo system components (Epo, Epo-R and betac) during neurodegenerative processes following pilocarpine-induced status epilepticus (SE), and examined whether recombinant human Epo (rHuEpo) could support neuronal survival. We evidence that Epo is induced in astroglia following SE, in particular within areas displaying delayed neuronal death. In addition, we demonstrate for the first time that rHuEpo reduces considerably hippocampal neurodegeneration following SE. rHuEpo may thus supplement astroglial induction of Epo to promote enhanced hippocampal neuronal survival following SE. We also show that Epo-R is expressed by neurons and astrocytes mainly, while betac is barely detectable in basal conditions and induced in reactive microglia exclusively following SE. Altogether, our results suggest that Epo/rHuEpo exerts neuroprotection, through Epo-R signaling and independently of betac, and, therefore, may be anti-epileptogenic.