Although EphA3 expression has been associated with progression or prognosis in several types of tumors, the role of EphA3 in hepatocellular carcinoma (HCC) remains unknown. This study sought to investigate the clinicopathological and prognostic relevance of EphA3 expression in HCC as well as the underlying mechanisms responsible. EphA3 protein was mainly localized within the cytoplasm and at the cell membrane. High EphA3 expression was correlated with tumor size, tumor grade, metastasis, venous invasion and AJCC TNM stage (P<0.05), and patients with high levels of EphA3 expression were at a significantly increased risk for shortened survival time (P<0.05). In vitro, the downregulation of EphA3 expression decreased the invasive capacity of HCC cells via the regulation of VEGF. EphA3 may represent a novel candidate marker for patient prognosis as well a molecular target for HCC therapy.