SUMOylation has emerged as an important post-translational modification that modulates the localization,stability and activity of a broad spectrum of proteins. A dynamic process, it can be reversed by a family of SUMOspecificproteases (SENPs). However, the biological roles of SENPs in mammalian development and pathogenesisremain largely elusive. Here, we demonstrated that SENP2 plays a critical role in the control of hepatocellularcarcinoma cell growth. SENP2 was found to be down-regulated in hepatocellular carcinoma (HCC) tissues andover-expression suppressed the growth and colony formation of HCC cells. In contrast, silencing of SENP2 bysiRNAs promoted cancer cell growth. We further found that stability of β-catenin was markedly decreasedwhen SENP2 was over-expressed. Interestingly, the decrease was dependent on the de-SUMOylation activity ofSENP2, because over-expression of a SENP2 catalytic mutant form had no obviously effects on β-catenin. Ourresults suggest that SENP2 might play a role in hepatocellular carcinoma cell growth control by modulating thestability of β-catenin.