We sought to study the presence of the receptor for advanced glycation endproducts (RAGE) and its ligands, advanced glycation endproducts (AGEs), S100/calgranulins and amphoterin (high mobility group box 1 protein; HMGB1), in the vitreous cavity and epiretinal membranes (ERMs) of eyes of patients with proliferative diabetic retinopathy (PDR) and proliferative vitreoretinopathy (PVR). Undiluted vitreous specimens were collected from 30 eyes of 30 patients undergoing pars plana vitrectomy for repair of retinal detachment (RD) secondary to PDR (n = 15) or PVR (n = 15). The vitreous samples obtained from 10 eyes undergoing macular hole repair were used as controls. Epiretinal membranes were obtained from eight eyes with PDR and from 10 eyes with PVR. The levels of AGEs in the vitreous were measured using ELISA. The vitreous levels of soluble RAGE (sRAGE), S100/calgranulins and amphoterin were measured using Western blot analyses. The localization of RAGE and its ligands in ERMs was determined with immunohistochemistry. The vitreous levels of sRAGE were significantly increased in both PDR and PVR (p < or = 0.05) compared to control vitreous. In both PDR and PVR, the vitreous levels of AGEs (p < or = 0.01), S100/calgranulins (p < or = 0.05), and amphoterin (p < or = 0.01) were also elevated compared to control eyes. Expression of RAGE was detected in six of eight ERMs from eyes with PDR and eight of 10 ERMs from eyes with PVR. Many cells expressing RAGE also expressed vimentin, suggesting a glial cell origin. Ligands for RAGE were also detected in ERMs, with AGEs detected in five eyes with PDR and eight eyes with PVR. Similarly, S100 and amphoterin ERM expression was observed in six eyes with PDR; these ligands were also expressed in ERMs from eyes with PVR (8 and 7 cases, respectively). We conclude that RAGE and its ligands are increased in the vitreous cavity of eyes with PDR and PVR and are present in ERMs of eyes with these proliferative retinal disorders. These findings suggest a role for the proinflammatory RAGE axis in the pathogenesis of proliferative retinal diseases.