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Indocyanine green (ICG) dye was shown to improve the visualization of preretinal tissues during chromovitrectomy. However, controversy arose regarding the safety of intravitreal ICG application, because worse functional outcomes and a higher incidence of retinal pigment epithelium (RPE) changes and visual field defects were reported. The mechanisms of ICG-related toxicity and their relevance for chromovitrectomy are reviewed.A literature search was performed from 1998 through 2005 for relevant information related to the mechanisms of intravitreal ICG toxicity. Animal and clinical data on intravitreal ICG-related toxicity were collected to clarify the mechanisms of the risk of intravitreal ICG injection.Over 80 controversial in vitro, ex vivo, and in vivo animal investigations as well as clinical reports on intravitreal ICG staining were found in the literature. The main postulated mechanisms of intravitreal ICG-related toxicity were as follows: biochemical direct injury to the ganglion cells/neuroretinal cells, RPE cells, and superficial retinal vessels; apoptosis and gene expression alterations to either RPE cells or neuroretinal cells; osmolarity effect of ICG solution on the vitreoretinal interface; light-induced injury; and mechanical cleavage effect to the internal limiting membrane/inner retina. Whereas the exact mechanism of intravitreal ICG-related damage remains yet to be determined, most animal experiments proposed that ICG dye has a dose-dependent toxic effect on retinal tissue. This hypothesis was supported by clinical data, because better functional outcomes were obtained when low dye concentrations and short incubation times were reported.Much evidence supports that ICG dye has a dose-dependent toxic effect on the retina. Therefore, the following recommendations to minimize toxic effects on the retina are proposed: dye injection in concentrations as low as possible; avoidance of repeated ICG injections onto bare retina; dye injection far from the macular hole to prevent direct dye contact with the RPE; short incubation time of ICG in the vitreous cavity to diminish the concentration in contact with the retinal tissue; and the light pipe kept far from the retina throughout the whole surgical procedure.