14-3-3 proteins have been reported to interact with numerous intracellular signaling molecules in regulation of various cellular functions. 14-3-3β has been shown to be associated with integrinβ1 to enhance cell adhesion and migration. However, its role on tumor progression and cancer metastasis has not been well investigated. Here, we report that overexpression of 14-3-3β significantly promotes hepatocellular carcinoma (HCC) cell growth and increase cancer cell anchorage-independent growth. Furthermore, an enhanced migratory capacity of both 14-3-3β- and integrinβ1-overexpressing cells was observed suggesting their importance in regulating cell adhesion and migration. In clinical trials, we analyzed the correlation of 14-3-3β in primary and subsequent metastatic tissues of HCC patients with its relevance in clinic-pathological parameters. 14-3-3β is overexpressed in primary tumors and predicts a higher 5-year incidence of subsequent metastasis. Additionally, expression of 14-3-3β is significantly correlated with a worse 5-year overall survival. Taken together, these findings reveal that 14-3-3β overexpression promotes tumor progression, and is associated with subsequent extrahepatic metastasis and worse survival. 14-3-3β might serve as a potentially prognostic biomarker and therapeutic target for HCC