A substantial percentage (30-70%) of human breast carcinomas that initially respond to endocrine therapy acquire resistance during the treatment. Many patients with tumor progression despite treatment with anti-estrogen tamoxifen show continued expression of estrogen receptors (ER) and/or progesterone receptors (PgR) in the relapse tissue. This indicates that, in these tumors, mechanisms other than loss of ER expression are responsible for treatment failure. We have investigated the occurrence and frequency of the exon-5-deletion variant (d5) of ER in human breast-cancer biopsies and in normal tissues. In all normal and tumor tissues tested, both wild-type (wt) and d5 were detected, indicating that expression of the d5 variant is a naturally occurring polymorphism. However, the primary tumors of patients who relapse within 15 months (n = 13) express higher ratios of d5 than do those of patients with no relapse during the same period (p = 0.4, n = 19), though this difference is statistically not significant. A significant increase in the expression level of d5 was determined in relapse as compared with the respective primary tumor (p = 0.02). These data indicate that increased expression of the ER exon-5-deletion variant in relapse tissues might be due to clonal selection of cells resistant to anti-estrogen treatment.