Background: To describe the presence of epiretinal proliferation in eyes with various retinal and vitreoretinal interface conditions. Methods: Consecutive patients seen at the Stein Eye Institute, by one retina specialist, from December 2018 to March 2019, and demonstrating epiretinal proliferation on optical coherence tomography (OCT) were enrolled in this cross-sectional study. Included patients were divided into two groups: vitreoretinal interface pathologies group or retinal diseases group. Presence of epiretinal proliferation and its localization within the 9 macular sectors, as defined by the Early Treatment Diabetic Retinopathy Study (ETDRS), were assessed on OCT. Results: 77 eyes from 69 patients demonstrated epiretinal proliferation on OCT. The most frequently involved ETDRS sector was the 1-mm central subfield, followed by inner temporal and inner nasal sectors. Localization of epiretinal proliferation correlated with the presence of any retinal abnormalities in the same quadrant (r = 0.962; P < 0.0001). 31 eyes (40.3%) demonstrated symptomatic vitreoretinal interface pathologies including lamellar macular hole, full-thickness macular hole, epiretinal membrane and history of macular peeling. 46 eyes (59.7%) manifested various retinal diseases, including age-related macular degeneration, diabetic retinopathy, refractory macular edema, vein occlusion and high myopia. Conclusions: Epiretinal proliferation was noted in several retinal conditions and not limited only to full-thickness and lamellar macular holes. Different mechanisms affecting retinal homeostasis might trigger Müller cells dysregulation, potentially leading to abnormal retinal remodeling.