Silicone-fluorosilicone copolymer oil has low viscosity (175-185 cSt) and is heavier than water (density, 1.16 g cm-3). Short term retinal tolerance (within 2 months) of the silicone-fluorosilicone copolymer oil has been reported to be the same as that of currently used intraocular silicone oil. Ocular response of the purified silicone-fluorosilicone copolymer oil were examined clinically and histopathologically from 2.5 months to 6 months after vitreous cavity injection in rabbit phakic eyes, and compared the oil tolerance with that of purified silicone oil (0.97 g cm-3, 5000 cSt). The effects in anterior chamber also were examined within 4 weeks of the silicone-fluorosilicone copolymer oil injection in different rabbits. Silicone-fluorosilicone copolymer oil recovered from the vitreous cavity at 6 months was analysed for cholesterol and retinol content by high performance liquid chromatography. Because of its low viscosity, silicone-fluorosilicone copolymer oil was easy to inject and remove from the vitreous cavity with a 20-G needle. After the vitreous injection, discrete droplet formation by the silicone-fluorosilicone copolymer oil occurred more easily than by silicone oil. Medullary ray detachment was seen in a silicone oil-, and some silicone-fluorosilicone copolymer oil-injected eyes at 4-6 months. Histopathologically, after 3-6 months disappearance of outer plexiform layer and disorganization of the photoreceptor layer of silicone oil-, and silicone-fluorosilicone copolymer oil-injected eyes were seen in the superior and the inferior retina, respectively. Migration of the photoreceptor cell nuclei to the photoreceptor layer was found in the inferior retina of silicone-fluorosilicone copolymer oil-injected eyes at 5-6 months. Small droplets ingested by mononuclear cells were found in the vitreous cavity or preretina at 4-6 months in silicone-fluorosilicone copolymer oil-injected eyes. After the anterior chamber injection, silicone-fluorosilicone copolymer oil induced endothelial cell damage in the area where the oil contacted continuously. Retinol and cholesterol were identified in silicone-fluorosilicone copolymer oil removed from the vitreous cavity. Silicone-fluorosilicone copolymer oil may be useful as an intraoperative device in retinal detachment surgery and as a short term (up to about 2 months) retinal tamponade but we do not recommend it for long term retinal tamponade.