Addition of sodium butyrate (NaB) to 6 cultured human breast carcinoma cell lines results in a dose and time-dependent growth inhibition. Kinetic evidence, related to the growth of a minority cell population which decreases in size with time of exposure, is presented to indicate that the NaB effect is reversible. In those cell lines that express the estrogen receptor (ER), growth inhibition is accompanied by a more differentiated phenotype, which is characterized by increased accumulation of lipid and milk-fat globule membrane glycoproteins. The potential for differentiation is not blocked by tamoxifen, indicating that the relationship to ER expression is likely secondary to the association of ER expression with a particular stage of secretory cell differentiation that is susceptible to NaB induction. Of the 3 lines shown to respond in this way (MCF-7, ZR-75-1, and MDA-134), ZR-75-1 is an extreme example that may serve as a model for studies of gene expression during human mammary epithelial cell differentiation.