In a continuing effort to improve the subtype selectivity and agonist potency of estrogen receptor β (ERβ) ligands, we have designed and developed a thus far unexplored structural series obtained by molecular refinements of monoaryl-substituted salicylaldoximes (Salaldox B). The most interesting compounds in this series (2c,d) show remarkably high ERβ-binding affinities, with Ki values reaching the sub-nanomolar range (Ki = 0.38 nM for 2c and 0.57 nM for 2d), and have very high levels of ERβ-subtype selectivity. Both compounds show a potent full-agonist character on ERβ (EC50 = 0.23 nM for 2c and 1.3 nM for 2d). Furthermore, 2d shows a remarkable functional subtype-selectivity, with a β/α transcription potency ratio 50-fold higher than that of estradiol.