Previous investigations have examined the role of serum and retinal pigment epithelium-derived factors in the elaboration of epiretinal membranes. Alternatively, the contribution of the insoluble interphotoreceptor matrix, known to contain chondroitin-sulfate-containing proteoglycans, in the generation of epiretinal membranes, has not been evaluated, to our knowledge. To investigate the potential role of chondroitin sulfates in eliciting epiretinal membranes, chondroitin sulfate glycosaminoglycans were injected into the vitreous cavity of rabbits. Examination demonstrated epiretinal membranes in 86% of eyes receiving chondroitin-6-sulfate. Temporal development of chondroitin sulfate glycosaminoglycan-induced epiretinal membranes was categorized into three distinct stages: a preretinal cell stage 1 to 3 weeks following injection, a glial "tuft" stage at 3 to 6 weeks, and a "mature" complex membrane stage at 6 weeks or later. Our results suggest that intravitreal administration of chondroitin sulfate glycosaminoglycan, components of insoluble interphotoreceptor matrix proteoglycans, may elicit the generation of epiretinal membranes, even in the absence of retinal disruption.