We describe a reproducible animal model of epiretinal proliferation, based on intravitreal injection of red blood cells, that closely simulates the more benign proliferative extraretinopathies. Using light microscopy and scanning and transmission electron microscopy, we monitored the development and behavior of the experimental epiretinal membranes. We found breaks in the integrity of the retinal surface through which glial cells migrated onto the retina, proliferated into thick epiretinal tissue, and contracted to cause retinal pucker. All these steps were associated with the chronic inflammatory response to the long-lasting presence of red blood cells in the vitreous. Thus, the development of epiretinal membranes requires continuous intraocular stimulation in addition to a break in retinal integrity.