Differentiation of keratinizing epithelia results in the formation of an exterior cornified layer that is both sufficiently cohesive to provide a protective barrier and dyshesive enough to permit orderly, apical desquamation. Membrane glycoconjugates, which are of presumed importance for intercellular adhesion and growth control, have recently been visualized in mouse, rat, and human epidermis. Because retinoids are known to profoundly influence epidermal differentiation, the lectin-staining pattern in normal mouse epidermis was compared to that observed in mice treated with etretinate (Ro 10-9359, 50 mg/kg/day). Within 2 days of treatment with 50 mg/kg/day of etretinate, abnormal transepidermal water loss began, followed by mild acanthosis after 4 to 6 days, and focal loss of stratification by 10 days. Despite these dramatic alterations in structure and function, abnormalities in lectin staining first appeared only after 15 days. Both wheat germ agglutinin and succinyl wheat germ agglutinin stained an etretinate-dependent product localized in the granular layer in samples treated for 21 to 38 days. Both the intensity and the distribution of PNA (galactose-N-acetyl-galactosamine) and Ulex (α-L-fucose) staining were affected by retinoid treatment, but the staining pattern with other lectins was not altered until 40 to 45 days, at which time the sugars in some samples were either restricted to isolated nests of cells or greatly diminished. Although etretinate appeared to provoke selective changes in keratinocyte membrane glycoconjugates, these alterations became apparent only after the retinoid had profoundly perturbed epidermal differentiation. These altered patterns may not only reflect retinoid-induced aberrations in cohesion and barrier function, but also may provide clues about the role of certain membrane sugars in the control of normal epidermal differentiation.