After resurfacing a total corneal epithelial defect extending 2-3 mm beyond the limbus, conjunctival epithelium gradually loses goblet cells and transforms into a corneal-like epithelium. We examined the effect of topical retinoic acid on the reversal of transdifferentiation on nonvascularized corneas. Four months after total denudation of corneal epithelium using n-heptanol, rabbit corneas without vascularization received topical drops of 0.1% (wt/vol) all-trans retinoic acid in corn oil 3 times a day. Before treatment, the transdifferentiation was complete, as evidenced by the absence of goblet cells on the corneal surface using a topographical assay and routine histology. After treatment for 15 days, goblet cells reappeared 3 mm into the peripheral cornea, and extended in a centripetal density to 4.5 mm after 32 days. To prove that retinoic acid was not angiogenic, retinoid-bearing Elvax-40 pellets were implanted into normal corneal stroma. Taken together, these data indicate that vitamin A or retinoids may be an important factor in the modulation of conjunctival epithelial transdifferentiation.