In this study we have introduced the 11beta-methoxy group, a substituent known to increase in vivo potency in other steroidal estrogens, into the (17alpha,20E)-21-(trifluoromethylphenyl)-19-norpregna-1,3,5(10),20-tetraene-3,17beta-diols: (trifluoromethylphenyl)vinyl estradiols. Receptor binding, using the ERalpha-HBD, indicated that the 11beta-methoxy group had little effect on the relative binding affinity of the target compounds compared to the corresponding 11beta-unsubstituted analogs, however, the 11beta-methoxy derivatives were significantly more potent in stimulating uterotrophic growth in immature female rats. Molecular modeling studies suggest that while the 11beta-methoxy group does not contribute significantly to the overall binding energy of the ligand-ERalpha-HBD complex, it stabilizes residues associated with the coregulator protein binding site. Such effects would influence the dynamics of subsequent events, such as transcription and biological responses.