BACKGROUND Lysine-specific demethylase 5B (KDM5B) is overexpressed in several types of cancer. However, the clinical significance of KDM5B expression in hepatocellular carcinoma (HCC) remains unclear. The aims of the present study were to examine the functional effects of KDM5B in the Hep3B cell line, the expression levels of KDM5B in human HCC tissues, and the association between KDM5B expression and clinical outcome in patients with HCC. MATERIAL AND METHODS Immunohistochemistry (IHC) and quantitative real-time polymerase chain reaction (qRT-PCR) were used to examine the expression levels of KDM5B in HCC tissues and adjacent normal liver tissues. In the HCC cell line, Hep3B, the effects of KDM5B on cell proliferation and migration, and KDM5B small interfering RNA (siRNA) were used to study KDM5B knockdown. Univariate and multivariate analysis assessed the prognostic role of KDM5B in HCC patients. Kaplan-Meier analysis and the log-rank test evaluated clinical outcomes. RESULTS In the HCC cell line, Hep3B, KDM5B expression promoted promote tumor cell proliferation and colony formation. Increased expression of KDM5B in HCC tissues, compared with adjacent normal liver tissues, and was associated with larger tumor size, advanced TNM stage, and reduced overall survival in patients with HCC. Multivariate analysis identified KDM5B expression as an independent prognostic factor. CONCLUSIONS Increased expression of KDM5B was significantly correlated with poorer prognosis in patients with patients with HCC, indicating the possible potential of KDM5B as a novel clinical biomarker and therapeutic target.