Abstract Oral squamous cell carcinoma (OSCC) is a globally prevalent malignancy. The molecular mechanisms of this cancer remain to be elucidated to acquire further interception. Peroxiredoxin like 2A (PRXL2A) was named FAM213A previously, has been reported an antioxidant protein that protects cells from oxidative stress. Our previous study has identified the association between PRXL2A up-regulation in OSCC and the worse prognosis of patients. MicroRNAs (miRNAs) are small non-coding RNAs involved in the modulation of physical or pathological properties. miR-125 family genes drive pluripotent regulation in a wide variety of cancers. In this study, we specified the oncogenic eligibility of PRXL2A and clarified miR-125b as its upstream regulator. Down-regulation of miR-125b was observed in OSCC tumors. Lower miR-125b expression in OSCC tissues defined the worse patient prognosis. Reporter assays validated that PRXL2A as a direct target of miR-125b. Exogenous miR-125b expression resulted in the decreased oxidative stress, increased drug sensitivity, and suppressor activities, which was consistent with the knockout of PRXL2A gene in OSCC cells. That the suppressor activities of miR-125b being rescued by PRXL2A denoted the existence of miR-125b-PRXL2A regulatory axis in OSCC pathogenesis. Knockout of PRXL2A drastically attenuated the tumorigenic potential of OSCC cells. Overall, this study proposes novel clues demonstrating that the down-regulation of miR-125b suppressor underlies the PRXL2A up-regulation in OSCC, and this protects tumor cells from oxidative stress leading to the worse patient survival. Citation Format: Yi-Fen Chen, Yun-Yen Wei, Cheng-Chieh Yang, Chung-Ji Liu, Kuo-Wei Chang, Shu-Chun Lin. miR-125b mediates oral cancer suppression by targeting the antioxidative gene peroxiredoxin like 2A (PRXL2A) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4422.