Rho GTPase-activating proteins (RhoGAPs) are implicated in the development and progression of hepatocellular carcinoma (HCC). We tested the idea that RICH2 is a tumor suppressor in HCC. Consistent with this, RICH2 was downregulated in HCC and HCC cell lines and RICH2 expression negatively correlated with the tumor size, TNM stage and metastasis in HCC. RICH2, in a Cdc42 dependent manner, regulated the formation of filopodia in HCC and stable overexpression of RICH2 significantly inhibited the clone formation, proliferation and invasion of HCC cells in vitro. Gene set enrichment analysis (GSEA) showed that the expression of RICH 2 positively correlated with the expression of WNT5a, that exert antagonistic effect on canonical WNT signalling whereas RICH2 expression inversely correlated with the expression of β-catenin (CTNNB1), that is involved in the proliferation and invasion HCC. These findings concurred with co-immunoprecipation of RICH2 with endogenous Cdc42, Rac1, and β-catenin. Finally, RICH2 overexpression suppressed tumor growth in vivo. The findings support the idea that RICH2 might act as a tumor suppressor in HCC.