Background Erythropoietin (EPO) has a protective effect on retinal neurons in many retinal diseases,but regarding the effect of EPO on apoptosis of retinal photoreceptor cells in retinal detachment (RD) is uncompletely clear.Objective This study was to investigate the protective effect of endogenous EPO on photoreceptors in a rat model of RD and explore its possible mechanism.Methods Seventy-two Sprague- Dawley (SD) rats were randomly assigned to control group,RD group,RD+PBS group,RD+erythropoietin soluble receptor (EPOsR) 2, 20, 200ng groups with 12 rats for each group.1.4% hyaluronic acid was slowly injected into the subretinal space to induce RD in rats,and PBS or 2,20 or 200ng EPOsR was then injected into the vitreous space.On day 3 after RD,apoptotic photoreceptors were detected using transferase-mediated dUTP nickend labeling (TUNEL),and caspase-3 activity was assessed by Western-blot and immunofluorescence staining.On day 14 after RD,retinal histopathologic examination was carried out and outer nuclear layer (ONL) thickness was measured under the light microscope.The use of animals complied with the Statement of Association for Research in Vision and Ophthalmology. Results Apoptotic photoreceptors were seen in ONL of rats of the RD group.Apoptotic photoreceptors were gradually increased with the elevation of EPOsR dose in the vitreous cavity.Western blot and immunofluorescence consistently showed that the gray scale of caspase-3 activity was 0.15±0.04,0.49±0.03,0.50±0.07,0.63±0.03,0.69±0.04 and 0.83±0.04 in the normal group,RD group,RD +PBS group,RD+EPOsR 2,20,200ng groups respectively with statistically significant differences (F=76.016;P=0.000),and caspase-3 activity was considerably stronger in the RD+EPOsR 200ng group than the other groups (P＜0.01).On day 14 after RD,the ONL thicknesses in the normal control group,RD group,RD+PBS group,RD+EPOsR 2,20,200ng groups were (47.39±3.39)μm,(33.96±3.54)μm,(31.83±5.21)μm,(31.40±2.63)μm,(24.99±2.06)μm and (19.30±3.71)μm,showing significant differences among these groups (F=44.733,P=0.000).ONL thicknesses the groups treated with different doses of EPOsR were markedly thinner than that of the RD group and RD +PBS group (P＜0.01).Conclusion EPOsR induces apoptosis of retinal cells and enhances the activity of caspase-3 in a dose-dependent manner.Endogenous EPO can protect photoreceptors against anoxia-mediated damage in RD eyes through decreasing caspase-3 activity and inhibiting apoptosis.