The effect of oral aromatic retinoid Ro 10-9359 in a high dosage (25 mg/kg/day) on guinea pig epidermis was investigated by light and electron microscopy. The induced morphological alterations showed two different stages: (a) In the injury stage, seen aftr one week of retinoid administraion, the epidermis was mainly characterized by lack of the horny layer and vacuolar cytoplasmic disintergration of the malpighian layer with intracellular edema and accumulation of some PAS-positive material. Tonofilaments and desmosomes were markedly reduced, keratinosomes were increased in number. (b) In the recovery stage, seen after 3 weeks of administration, the horny layer had reappeared, the edematous and vacuolar changes were diminished and the epidermis became slightly acanthotic. Hypergranulosis with numerous spongiform keratohyalin granules was a prominent feature. The number of tonofilaments, desmosomes, and keratinosomes showed a clear tendency to normalization. In conclusion, high systemic doses of aromatic retinoid initially exert a cytotoxic, keratolytic, and mucoplastic effect on the normal guinea pig epidermis. Nevertheless, the affected keratinocytes adapt themselves, despite the further administration of the drug, showing a gradual restoration of these changes and a stimulation of epidermal proliferation, leading to acanthosis.