||Several studies indicate that erythropoietin (EPO) has remarkable neuroprotective effects in various central nervous system disorders, while little is known about the effects of EPO in diabetes-associated cognitive dysfunction. Therefore, the present study aimed to investigate whether EPO ameliorates diabetes-associated cognitive dysfunctionin vivoandin vitro. We investigated the protective effects of EPO on high-glucose (HG)-induced PC12 cell death and oxidative stress. The effects of EPO (30065U/kg administered three times a week for 4 weeks) on diabetes-associated cognitive decline were investigated in diabetic rats. EPO significantly increased cell viability, increased the activity of superoxide dismutase, decreased the production of malondialdehyde and reactive oxygen species, and decreased the apoptosis rate. Additionally, LY294002, a phosphatidylinositol 3-kinase (PI3K) inhibitor, abolished the protective effects of EPO in HG-treated PC12 cells. In diabetic rats, EPO prevented deficits in spatial learning and memory in the Morris water maze test. The results of real-time PCR and Western blotting showed that EPO upregulated EPO receptor, PI3K, and phosphorylated Akt2 relative to unphosphorylated Akt2 (p-Akt2/Akt2) and downregulated glycogen synthase kinase-3β (GSK-3β). These studies demonstrate that EPO is an effective neuroprotective agent in the context of diabetes-associated cognitive dysfunction and show that this effect involves the PI3K/Akt/GSK-3β pathway.