Purpose: The AMP-activated protein kinase (AMPK) serves as an energy sensor in eukaryotic cells and occupies a central role in linking metabolism and cancer development. However, the phosphorylation status of AMPK and its therapeutic value in human hepatocellular carcinoma (HCC) remain unclear. Experimental Design: The phosphorylation status of AMPK (Thr172) was determined by immunoblotting and immunostaining in specimens from 273 patients with HCC (including 253 patients with hepatitis B virus -related HCC). Kaplan-Meier survival analysis was used to determine the correlation with prognosis. The effects of therapeutic metformin/AMPK activation were assessed in cultured human HCC cell lines and primary HCC cells in vitro and in xenograft tumors model in vivo. To define the mechanisms of anticancer effects of metformin, we examined its influence on AMPK activation and NF-kB pathway. Results: AMPK is dysfunctional in patients with HCC, and low p-AMPK staining is correlated with aggressive clinicopathologic features and poor prognosis. Activation of AMPK by metformin not only inhibited HCC cells growth in vitro and in vivo, but also augmented cisplatin-induced growth inhibition in HCC cells. Knockdown of AMPKa expression can greatly decrease the inhibitory effect of metformin, indicating that AMPK activation is required for the anticancer action of metformin. Mechanistically, metformin/AMPK activation inhibited NF-kB signaling through upregulation of IkBa. Activation of NFkB signaling by ectopic expression of P65 or overexpression of an undegradable mutant form of IkBa attenuated the anticancer effects of metformin. Conclusions: These results present novel insight into a critical role of AMPK in HCC progression. Anticancer effects of therapeutic metformin/AMPK activation unravel metformin?s potential in treatment of HCC.