Recent data suggest that the expression of estrogen receptor (ER) variants may be common in clinical breast cancer. The significance of their expression is complicated by the fact that they are often coexpressed with wild-type ER in the same tumor. We have focused upon one such ER variant which lacks exon 5 within the hormone binding domain of the receptor. This deletion introduces a stop codon, resulting in a truncated ER of 40 kDa which is unable to bind hormone. We have been exploring the hypothesis that this variant may contribute to clinical antiestrogen resistance. Coexpression of the exon 5 variant along with wild-type ER in MCF-7 human breast cancer cells confers resistance to the commonly used antiestrogen, tamoxifen. In addition, we have observed that some metastatic breast lesions overexpress exon 5 ER deletional variant transcripts. We conclude that differences in the relative amounts of several ER variants in the same tumor may interact to determine hormonal responsiveness and metastatic behavior.