To investigate the potential prognostic value of osteopontin (OPN) in hepatocellular carcinoma (HCC) patients after hepatectomy. A total of 384 HCC specimens with paired adjacent non-tumorous tissues from liver resections were collected to construct a tissue microarray for immunohistochemistry (IHC) analysis to detect the expression of OPN. OPN expression was semi-quantified with scores according to IHC staining. The potential correlations between OPN expression and neoplastic features of HCC were analyzed. The survivals in patients stratified with different OPN expression levels were calculated and compared. Uni-and multi-variate analysis were conducted to identify the potential prognostic value of OPN in HCC patients received liver resections. The OPN in HCC tissues was 0.82±0.68, significantly higher than that in matched nontumorous tissue (0.45±0.59; P< 0.001). Higher OPN expression was associated with vascular invasion (P= 0.019). Patients with high OPN expression had worse overall survival (P< 0.001), disease-free survival (P= 0.045) and higher probability of recurrence (P= 0.048), compared with the patients of low OPN expression. Multivariate analysis indicated that OPN expression was an independent risk factor for overall survival (P= 0.045), disease-free survival (P= 0.048), and HCC recurrence (P= 0.044). OPN expression was elevated in HCC tissues. High OPN expression was correlated with HCC vascular invasion. High OPN expression in HCC tissues is an independent factor for DFS and OS. OPN could be a predictor of HCC patients and a potential therapeutic target for the disease.