Background & Aims The transcription factor Krüppel-like factor 8 (KLF8) has a role in tumor development, growth, and metastasis, but its role in hepatocellular carcinoma (HCC) is not clear. Methods KLF8 expression in human HCC cell lines and tumor tissues was measured by quantitative real-time polymerase chain reaction, immunoblot, and immunochemical analyses. The effects of KLF8 depletion or overexpression in HCC cells were observed in cultured cells and in mice. Changes in gene expression patterns in HCC cells in which levels of KLF8 were reduced using small interfering RNA were investigated by microarray analysis. The clinical significance of KLF8 expression levels were validated using tissue microarray analysis of surgical samples from 314 HCC patients. Results KLF8 was overexpressed in highly metastatic HCC cell lines and in samples from patients with recurrent HCC. In cultured cells, KLF8 up-regulation promoted cell proliferation and invasion; inhibited apoptosis; down-regulated N-cadherin, vimentin, and fibronectin; and up-regulated E-cadherin. In mice, overexpression of KLF8 increased HCC progression and metastasis. Microarray analysis showed that reduction of KLF8 in HCC cells down-regulated expression of multiple genes involved in tumor progression and metastasis. KLF8 expression was a significant predictor of overall survival ( P = .040) and time to HCC recurrence ( P = .006) and was associated with early tumor recurrence ( P = .001). Conclusions KLF8 promotes HCC cell proliferation and invasion, inhibits apoptosis, and induces the epithelial-to-mesenchymal transition. KLF8 up-regulation might be used to indicate poor prognosis or early recurrence of cancer in patients who have had surgery for HCC.