Our SNP-Chip data demonstrated 7/60 (12%) hepatocellular carcinoma (HCC) patients had PRL-1 copy number amplification. However, its biological functions and signaling pathways in HCC are deficient. Here, we investigated its oncogenic function and prognostic significance in HCC. PRL-1 protein levels were examined in 167 HCC samples by immunohistochemisty (IHC). The relationship of PRL-1 expression and clinicopathological features was assessed by correlation, Kaplan-Meier and Cox regression analyses. The oncogenic function of PRL-1 in HCC cells and its underlying mechanism were investigated by ectopic overexpression and knockdown model. PRL-1 levels in primary HCC and metastatic intravascular cancer thrombus were also determined by IHC. PRL-1 levels were frequently elevated in HCC tissues (81%), and elevated expression of PRL-1 was significantly associated with more aggressive phenotype and poorer prognosis in HCC patients (p<0.05). Ectopic overexpression of PRL-1 markedly enhanced HCC cells migration and invasion. Furthermore, the oncogenic functions of PRL-1 were mediated by PI3K/AKT/GSK3β signaling pathway through inhibiting E-cadherin expression. Finally, PRL-1 protein levels in metastatic cancer thrombus were higher than that in primary HCC tissues (p<0.05). These data highlight the oncogenic function of PRL-1 in HCC invasion and metastasis implicating PRL-1 as a potential prognostic marker as well as therapeutic target in HCC.