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Proliferative diabetic retinopathy (PDR) is a major complication of diabetes characterized by pathological angiogenesis in the retina. Standard treatment includes vitrectomy to remove these abnormal vessels, and the resulting clinical specimens provide an opportunity to define drivers of PDR. Here, we profiled endothelial and immune cells from such samples to identify disease mechanisms. In some patients, endothelial cells were more abundant, whereas in others, immune cells predominated. Immune cells exhibited gene expression programs directed against pathological endothelium, suggesting an endogenous defense that may explain the scarcity of endothelial cells in certain cases. Preoperative anti-vascular endothelial growth factor (VEGF) therapy altered transcriptional programs in both endothelial and immune cells, indicating that its effects extend beyond the vasculature. A comparison of endothelial signatures from PDR patients and nondiabetic donor retinas revealed a distinct molecular program in PDR, prominently marked by mitochondrial dysfunction. In contrast, endothelial cells from the murine oxygen-induced retinopathy (OIR) model lacked mitochondrial dysfunction, although other features of pathological angiogenesis were shared. These findings suggest that PDR is not a uniform disease but comprises distinct types characterized by either immune-mediated clearance of pathological vessels or endothelial mitochondrial dysfunction. They also revealed that anti-VEGF therapy influences both endothelial and immune compartments, with implications for treatment strategies. Finally, the data clarify both the relevance and limitations of the OIR model for preclinical testing of new therapeutic targets.