We studied the repair of large, surgically induced retinal pigment epithelial defects in rabbit eyes for up to 28 days. Ophthalmoscopically, the pigment epithelium surrounding the defect became less pigmented and scattered pale foci appeared. The margin remained distinct for 28 days and the defect was subsequently covered by a variable lacework of pigmentation. Angiographically, the acute defect was hyperfluorescent and leaked heavily, but within 7 days fluorescein leakage had ceased. Histology, transmission and scanning electron microscopy, and autoradiography for the study of cells in division revealed that the pigment epithelium surrounding the defect became pleomorphic after 1 day, began to proliferate within 3 days, and covered the defect within 7 days. Subsequently, many cells became pigmented and some were fibrocyte-like. The cells within the healing defect appeared to have derived from the pigment epithelium. Our findings suggest that similar processes occur in large human defects such as pigment epithelial rips.