||Tissue-specific effects of progesterone are mediated by two isoforms of the progesterone receptor (PR), PR-A and PR-B, through direct transcriptional regulation in the nucleus and initiation of rapid signaling cascades in the cytoplasm. Two non-steroidal PR antagonists, PRA-348 and PRA-920, were found to function as potent antagonists at low concentrations ( 300 nM). Previous work indicates that these compounds antagonize PR by inhibiting nuclear translocation; however the isoform specificity of this effect is unknown. Luciferase assays were completed with T47D cells stably transfected with PR-A or PR-B and treated with PRA-348 and PRA-920 to measure PR-mediated transcriptional activity in an isoform specific manner. Western blot analysis was performed to assess changes in PR-A and PR-B localization and phosphorylation after treatment. Both PRA-348 and PRA-920 inhibited nuclear translocation and phosphorylation of both isoforms at concentrations below 300nM and induced nuclear translocation and phosphorylation at higher concentrations. This unique mechanism for PR antagonism enhances our understanding of PR function and aids in the development of new PR modulators that have the potential to treat various female reproductive disorders.