Hepatocellular carcinoma (HCC) is one of the most common cancers and the second leading cause of cancer related death worldwide. ZNF545 is located in the chromosome 19q13.13, which is frequent loss of heterozygosity in human astrocytoma. Methylation of ZNF545 was found frequently in a few kinds of cancers. While the function of ZNF545 in human HCC remains unclear. The purpose of this study is to explore the function and mechanism of ZNF545 in human HCC. Restoration of ZNF545 expression suppressed cell proliferation, migration and invasion, induced G1/S arrest and apoptosis in SNU449 and Huh7 cells. Further study suggested that ZNF545 suppressed HCC cell growth by inhibiting NF-kB signaling. These results were further validated by siRNA knocking down technique in ZNF545 highly expressed HXBF344 cells. In vivo, ZNF545 suppressed tumor growth in SNU449 cell xenograft mice. In conclusion, ZNF545 suppresses human HCC growth by inhibiting NF-kB signaling.