A single intravitreal injection of fluorouracil was effective in the treatment of an experimental model of massive periretinal proliferation. When given with an intravitreal injection of 250,000 heterologous fibroblasts, fluorouracil decreased the rate of tractional retinal detachment from 36.8% in controls (seven of 19 eyes) to 5.2% in treated animals (one of 19 eyes) at one week, and from 73.6% in controls (14 of 19 eyes) to 31.5% in treated animals (six of 19 eyes) after four weeks (P less than .05). Intraocular neovascularization was reduced from 52.6% in controls (ten of 19 eyes) to 5.2% in treated animals (one of 19 eyes) after one week and 36.8% in controls (seven of 19 eyes) to 5.2% in treated animals (one of 19 eyes) after four weeks. When supplemented by repeated 10-mg subconjunctival injections of fluorouracil, or in combination with intravitreally administered indomethacin, this effect appeared to be enhanced. Intravitreal and subconjunctival injections of fluorouracil were well tolerated and may prove to be of significant value in the treatment of human disease.