We report here the discovery that retinoids are potent regulators of epithelial morphology and keratin expression in cultured human mesothelial cells. When LP-9 cells are cultured in medium supplemented with vitamin A-depleted serum, they grow with an extreme spindle-shaped morphology and synthesize abundant levels of vimentin, but very little keratin. When retinoic acid is added to the medium at 1 X 10(-8) to 1 X 10(-6) M, keratin synthesis is increased, vimentin synthesis is decreased, and the cells assume an epithelioid morphology. Keratin synthesis, but not epithelioid morphology, seems to be dependent on cell density as well: even when vitamin A is present, sparse cultures cannot fully maintain keratin synthesis. In contrast, epidermal growth factor (EGF) acts in an antagonistic fashion to suppress both keratin synthesis and epithelial morphology. The effects of vitamin A, EGF, and cell shape on intermediate filament (IF) expression seem to occur in a growth-independent manner, and they appear to be at the level of transcription or mRNA stability. Even so, their effects on IF expression do not appear to be rapid ones, and hence it is unlikely that these agents interact directly at the gene level to cause changes in IF gene expression.