At high levels of vitamin A and other retinoids (3 X 10(-6) M) attachment of human keratinocytes to 3T3-coated plastic dishes is mildly inhibited. Retinoids at this concentration in culture media seem to have an antikeratinizing effect in that cells appear to be less differentiated. Retinoid-treated cultures are less stratified, having fewer cell layers, and display larger intercellular spaces and rounder, less flattened cells. Treated cultures also contain higher percentages of saline-soluble proteins and lower percentages of proteins requiring reduction and/or denaturants for solubility. This suggests that in treated cultures, the most keratinized cells are absent. Growth curves show that those most keratinized cells are sloughed from the dish and appear in the media. Thus at 3 X 10(-6) M, the major retinoid effect is to promote desquamation. At higher concentrations, retinoids are toxic to the keratinocyte, but at lower concentrations, they may be stimulative.