Background: The treatment of castration-resistant prostate cancer (CRPC) has changed dramatically with the use of two new therapies, enzalutamide and abiraterone, directed at the androgen receptor (AR) signaling axis. However, eventually almost all patients relapse after these agents because of acquired resistance by a variety of mechanisms such as AR overexpression, the occurrence of AR mutations, or the induction of AR splice variants that confer ligand independent AR transactivation. TAS3681 is an oral pure AR antagonist with AR down-regulating activity. In this study, we investigated the effect of TAS3681 on several issues related to resistance to current AR-targeted therapy. Methods: VCaP cells transfected with wild-type AR-expressing vector, which overexpress AR, were treated with TAS3681 in the presence of androgen. Cells were harvested and luciferase activity was determined. For the analysis of F876L mutant AR, LNCaP cells stably expressing F876L AR protein were incubated with TAS3681 in the presence of androgen. The WST-8 assay was performed to measure cell viability. Prostate cancer cells expressing AR-v7 were treated with TAS3681, and full length (FL)-AR and AR-v7 protein levels were determined by Western blot. TAS3681 was orally dosed to confirm AR down-regulation in tumor and evaluate antitumor efficacy in AR-v7 positive CRPC tumor xenograft mouse model. Results: In prostate cancer (PCa) cells which overexpress AR, in contrast to enzalutamide, TAS3681 effectively suppressed AR transactivation and cell proliferation via AR down-regulation. TAS3681 effectively antagonized F876L mutant AR which confers resistance to cell growth inhibition by enzalutamide. Moreover, TAS3681 reduced both FL-AR and AR-v7 protein level in PCa cells in vitro and in vivo, and showed strong antitumor efficacy in AR-v7 positive xenografts. Conclusions: TAS3681 disrupts the aberrant AR signaling via a novel mechanism of action: pure AR antagonism plus down-regulation of full-length and splice variant AR. These findings suggest that TAS3681 has the potential to overcome resistance to current AR pathway target drugs.