Retinal pigment epithelium (RPE) exerts critical roles in the maintenance of the normal functions of the retina, whereas RPE dysfunction can induce retina neovascularization. p75 neurotrophin receptor (p75(NTR)) has been shown to play essential roles in angiogenesis. However, the function of p75(NTR) in the RPE remains unclear. In the present study, we demonstrated that p75(NTR) was highly expressed in the human choroidal neovascularization membranes. For in vitro study, RPE was exposed to hypoxia, and a knockdown of p75(NTR) was achieved via lentivirus-mediated RNA interference. The results showed that hypoxia induced the expression of p75(NTR) in the RPE, and the knockdown of p75(NTR) rescued RPE proliferation activity and inhibited apoptosis which induced by hypoxia. After the deletion of p75(NTR), RPE-secreted pro-angiogenic factors (vascular endothelial growth factor and platelet-derived growth factor), inflammatory factors [interleukin 1 beta (IL1β), IL18, and stromal cell-derived factor 1], and matrix metalloproteinases (MMPs) (MMP3 and MMP9) were down-regulated under hypoxic conditions. While the RPE secreted anti-angiogenic factors (pigment epithelium-derived factor) and angiostatin, the tissue inhibitors of metalloproteinases (TIMPs) (TIMP-1 and TIMP-3) were up-regulated after the knockdown of p75(NTR). The human umbilical vein endothelial tube formation ability can be inhibited when it is co-cultured with the supernatant extract from p75(NTR)-knockdown RPE under hypoxic induction. These results suggest that the knockdown of p75(NTR) suppressed pro-angiogenic factors which induced by hypoxia while promoting the anti-angiogenesis-related factors in the RPE. It is indicated that p75(NTR) could be a potential therapeutic target for RPE hypoxia or oxidative stress diseases.