Silicone-fluorosilicone copolymer oil is characterized by being heavier than water (density, 1.16 g cm-3) and low viscosity (175-185 centistokes) compared with currently used intraocular silicone oils (density, 0.97 g cm-3 and 1000-5000 centistokes). This oil is potentially useful as an operative tool and a tamponade on the inferior retina in complicated retinal detachment. We evaluate the ocular response clinically and histopathologically within 8 weeks in rabbit phakic eyes to the purified silicone-fluorosilicone copolymer oil after vitreous cavity injection, and compared the oil tolerance with purified silicone oil (0.97 g cm-3, 5000 centistokes) and perfluorotetradecahydrophenanthrene for ophthalmic use (Vitreon, 2.03 g cm-3, 8.03 centistokes) which are currently used as operative tools and as internal retinal tamponade agents in retinal detachment surgery. Because of their low viscosity, silicone-fluorosilicone copolymer oil and perfluorotetradecahydrophenanthrene were easier to inject into the eye than silicone oil. Silicone-fluorosilicone copolymer oil and perfluorotetradecahydrophenanthrene occupied the inferior portion in the eye, and silicone oil occupied the superior portion. Fewer discrete oil droplets and weaker vessel attenuation of medullary rays than in the perfluorotetradecahydrophenanthrene-injected eyes were seen in silicone-fluorosilicone-copolymer-oil-injected eyes. Histopathologically, all retinas injected with silicone-fluorosilicone copolymer oil were normal within 4 weeks. The silicone-fluorosilicone copolymer oil dispersion did not induce histopathological changes within 8 weeks. However, thinning or disappearance of the outer plexiform layer was seen in the inferior retina in some silicone-fluorosilicone-copolymer-oil-injected eyes at 6-8 weeks. A similar effect was found in the superior retina of a silicone-oil-injected eye at 8 weeks. More severe changes such as thinning or disappearance of the outerplexiform layer, thinning and disorganization of the photoreceptor layer, and migration of the receptor cell nuclei to the photoreceptor layer were found in the inferior retina of perfluorotetradecahydrophenanthrene-injected eyes after 2 weeks. Intraocular silicone-fluorosilicone copolymer oil tolerance until about 2 months post-injection is similar to silicone oil and better than perfluorotetradecahydrophenanthrene. Silicone-fluorosilicone copolymer oil may be useful intraoperatively and as a temporary vitreous substitute in cases of inferior retinal detachment.