This study was designed to determine the safety and efficacy of transferrin–ricin A chain toxin (Tfr-rRA) at preventing retinal detachment in a rabbit model of proliferative vitreoretinopathy (PVR). The toxicity of intravitreal Tfr-rRA (1000–5000ng) was determined by indirect ophthalmoscopy and electroretinography on days 1, 5, 8, 16, 26 and 48 post-injection, and by light and transmission electron microscopy conducted on eyes enucleated 48 days after drug exposure. PVR was created by injecting 25000 homologous fibroblasts into the vitreous cavity of eyes which had previously undergone a gas compression vitrectomy. Eyes then received intravitreal Tfr-rRA (2000ng) or vehicle. Animals were examined on days 1, 4, 7, 10, 14, 21 and 28 post-injection. Intravitreal injection of 1000 and 2000ng Tfr-rRA did not show ophthalmoscopic or electroretinographic toxicity. Injection of 5000ng Tfr-rRA showed mild retinal whitening, retinal arteriolar narrowing, and electroretinographic toxicity, but no morphologic damage, such as photoreceptor loss, nuclear layer vacuolation, or inflammatory cell infiltration, to the retina. Tfr-rRA (2000ng) injected intravitreally 3 days after fibroblast injection prevented traction retinal detachment in 90% of eyes compared to 22% of sham treated eyes ( P< 0.001). The data from this study suggest that transferrin-ricin A chain toxin (2000ng) safely and effectively limits retinal detachment in experimental PVR.