PLZF-RARα is the second most frequent variant acute promyelocytic leukemia (APL) fusion protein that ranks after PML-RARα in APL. However, PLZF-RARα is resistant to current front line APL treatments including all transretinoic acid (ATRA), arsenic trioxide (ATO), and chemotherapy (i.e., Idarubicin). Herein, we for the first time report that phenylarsine oxide (PAO) could effectively induce PLZF-RARα variant fusion protein degradation through ubiquitin proteasome degradation pathway by apoptosis, which indicates that PAO might be a potential candidate for the treatment of PLZF-RARα variant APL. Given that, this study highlights the potential benefit of arsenic-organometallic compound PAO in APL treatment.