Three kinds of perfluorinated liquids (a perfluorooctane and two perfluoropolyethers) were evaluated as vitreous replacements. Tolerance to these liquids in rabbit eyes was investigated for periods of up to 2 months. Clinically, droplet formation of the liquids occurred within a few days of intravitreal injection. Histologic examination revealed no pathologic retinal changes 8 hours after surgery. At 6 days after surgery, hypertrophy of the Müller cells with bumplike protrusions into the interphotoreceptor space could be observed. At 1 month after surgery, light and electron microscopic examination showed larger droplike protrusions of Müller cells related to localized foldings of the outer retinal layers and rarefication of photoreceptor nuclei and loss of outer segments. Frequently disarranged, granule-loaded macrophages appeared in these areas. At 2 months after surgery, vesicles with low electron density appeared in some areas at the border between receptors and retinal pigment epithelium. In other areas pigment epithelial cells showed distinct hypertrophy (with drusen) toward the droplike Müller cell protrusion, together with narrowing of the interreceptor space. These findings were almost totally confined to the lower part of the retina that had been in permanent contact with the liquids. No histologic differences were noted between perfluorooctane- and perfluoropolyether-injected eyes. The results suggest that the liquids are not candidates for long-term vitreous replacement, but may be suitable for short-term intraoperative use.