The MCF-7 human breast cancer cell line is routinely used as a model system for the study of ER+, estrogen-responsive human breast cancer. Although most investigators have found these cells to be estrogen-responsive, there are reports that some stocks of MCF-7 cells may be either insensitive or may display decreased sensitivity to the mitogenic effects of estrogen. We report here that differences in estrogen responsiveness appear to be related to varying ratios of wild type to variant ER mRNAs. MCF-7 stocks which express a high ratio of wild type to variant ER transcripts are more responsive to the mitogenic effects of physiological concentrations of estradiol than stocks which express an elevated ratio of exon 5 deletion variant to wild type ER transcripts.