After retinal detachment the retinal pigment epithelium (RPE) undergoes a striking phenotypic change. It becomes dedifferentiated, proliferates to form multilayered colonies, and migrates into the subretinal space. These processes are important because they have been implicated in proliferative vitreoretinopathy and poor visual recovery after retinal reattachment; however the mechanisms by which they occur are unknown. In this study, the effect of retinoic acid on RPE cell morphology and growth in culture was examined. Cells grown in the presence of 1 microM retinoic acid do not exhibit cellular overgrowth and maintain characteristics associated with the morphologic appearance of mature RPE cells in vivo. Growth curves and 3H-thymidine incorporation suggest that retinoic acid inhibits RPE cell growth primarily after the cells have reached confluence. It may act by promoting density-dependent growth arrest. Dibutryl cyclic adenosine monophosphate also inhibits RPE cell growth and 3H-thymidine incorporation, but has little effect on cell morphology. However, in combination with retinoic acid it appears to have an additive effect on inhibition of cell growth and maintenance of a morphology like RPE in vivo. Retinoids have been demonstrated to modulate the growth and differentiation of several cell types. They are usually present in high levels in RPE cells. They become depleted in RPE in culture and such depletion may also occur in vivo after retinal detachment. This could play a role in the phenotypic alteration of RPE that occurs in association with retinal detachment.