Background: An evolutionarily conserved gene, the Salt-inducible kinase 1 (SIK1), functions to control mammalian life span and regulates human cells proliferation. However, the role of SIK1 in hepatocellular carcinoma (HCC) remains unclear. This study was aimed at investigating the expression pattern and clinicopathological significance of SIK1 in patients with HCC. Methods: The mRNA and protein expression levels of SIK1 were analyzed in eight HCC lines and eight paired HCC tumors by real-time PCR, Western blotting and immunohistochemical staining. Statistical analysis was used to evaluate the clinicopathological significance of SIK1 expression. Short hairpin RNA interfering approach was employed to suppress endogenous SIK1 expression in HCC cells to determine its role in proliferation. Results: SIK1 expression in liver cancer cell lines and tissues was significantly silenced at both the mRNA and protein levels compared with that in normal cells and adjacent non-tumorous liver tissues (ANT). SIK1 expression was strongly associated with HBsAg, AFP, tumor size, number of tumors, tumor encapsulation, vascular invasion, one year recurrence and five year recurrence. HCC patients with low SIK1 expression displayed a shorter overall survival and a higher recurrence rate than those with high SIK1 expression (P<0.05, respectively). Additionally, stable high-expression of SIK1 in HCC cells suppressed cell proliferation in vitro. Similarly, an in vivo assay showed that SIK1 up-regulation in hepatocellular carcinoma cells inhibited remarkably tumor proliferation potential in tumor size and weight. Conclusions: SIK1 protein may serve as a candidate prognostic marker and a novel therapeutic target for HCC and play an important role in inhibit proliferation and enhanced progression of HCC.