Normal human cells from epidermis and from buccal mucosa were cultured to confluence in three media with graded differentiation potential (at low Ca2+, high Ca2+, and supplemented with serum) and treated with transforming growth factor beta 1 (TGF-beta 1), as had been done previously with interferon-gamma (IFN-gamma). The response of the cells to TGF-beta 1 was monitored in terms of the expression of regulatory genes associated with proliferation and differentiation (cdc2, c-myc, p53) and of genes for structural proteins expressed at varying stages of maturation (keratins K5 and K10, involucrin, flaggrin). For both tissues, the results obtained with both agents were very similar for those genes expressed in the basal cells (cdc2, c-myc, p53, K5), regardless of their function, but diverged for the other genes, which are expressed in the suprabasal cells. Another related contrast is that, although IFN-gamma induced apoptosis in epidermal keratinocytes cultured in the serum containing medium, TGF-beta 1 did not. Thus, the two agents appear to affect the earlier stages of cell differentiation in the same way but to differ at the later stages, particularly in that IFN-gamma pushes maturation further than does TGF-beta 1).