OTUB1 (OTU domain-containing ubiquitin aldehyde binding protein 1) is a deubiquitinating enzyme (DUB) that belongs to the ovarian tumor (OTU) domain protease superfamily.Although it has been demonstrated to play important roles in the development of many kinds of cancer,the mechanism of OTUB1 in hepatocellular carcinoma (HCC) is not clear.The aim of this study was to explore the roles of OTUB1 in HCC progression using cell lines and 115 archived HCC samples.In addition,the clinical outcomes were also analyzed with a special focus on OTUB1 expression in HCC samples.In the immunohistochemical study,OTUB1 showed high expression in 60 of the 115 cases (52.2％).The OTUB1 expression level was significantly correlated with many clinicopathological parameters,including TNM stage (P =0.002),histology stage (P=0.002),and metastasis/recurrence (P =0.016).Survival analysis showed that the group with OTUB1 overexpression had significantly shorter overall survival time than the group with OTUB1 downregulation (hazard ratio [HR] =0.482;confidence interval [CI]:0.311-0.748;P =0.001).Multivariate analysis indicated that OTUB1 expression was a significant and independent prognostic parameter (HR =0.214;CI:0.126-0.364;P ＜ 0.001) for HCC patients.The ability of HCC cells to undergo proliferation,migration,and invasion was suppressed by disruption of endogenous OTUB1 using short hairpin RNA (shRNA).OTUB1 expression appears to be a new and independent predictor for the prognosis of HCC patients.Overexpression of OTUB1 in HCC could be a novel,effective,and supplementary biomarker for HCC because it plays a vital role in the progression of HCC.