The purposes of the current study were to investigate whether overexpression of the PRL-1 is clinically relevant to hepatocellular carcinoma (HCC) and whether expression patterns of PRL-1 in HCC have diagnostic and prognostic value.Immunohistochemistry analysis was performed for PRL-1 in 60 HCC samples. The data were correlated with clinicopathological features. The univariate and multivariate survival analyses were also performed to determine their prognostic significance.PRL-1 protein was overexpressed (83%) in HCC as compared with the adjacent normal tissue. PRL-1 expression was not influenced by chronic alcohol exposure or cirrhosis. High expression of PRL-1 was correlated with smoking (p=0.012), cirrhosis (p=0.047) and histological grade (p=0.055). The Kaplan-Meier survival curves showed that high PRL-1 expression related to a poor survival with statistical significance (I vs. III, p=0.010; II vs. III, p=0.001). Univariate analysis showed that PRL-1 expression was associated with tumour size, stage and PRL-1 score. Multivariate analysis revealed that the PRL-1 protein expression level was an independent factor for overall survival (HR, 5.367; 95% CI, 2.270-12.692; p=0.001). This is the first demonstration that the expression level of PRL-1 is correlated with tumour progression and prognosis in HCC.Along with other results, the PRL-1 protein is a candidate biomarker and a potential target for novel therapies against human HCC progression.