We aimed to evaluate the prognostic value of preoperative plasma osteopontin (OPN) levels in 101 patients with hepatocellular carcinoma (HCC) who underwent liver resection. Plasma OPN levels were detected by ELISA. The association of plasma OPN levels of patients with clinicopathological characteristics, tumor recurrence, and survival was analyzed. The median plasma OPN level of patients was 176.90 ng/ml (range 13.73-780.00 ng/ml), which was significantly higher than that of 24 healthy volunteers (63.74 ng/ml, range 12.20-122.32 ng/ml). Plasma OPN levels were significantly different in patients with different numbers of tumor nodules (168.18 and 217.11 ng/ml for single and multiple nodules, respectively; P = 0.002), different Edmondson's grades (201.24, 168.36, and 503.58 ng/ml for grades I, II, and III/IV, respectively; P = 0.015), and different TNM stages (168.16, 167.54, and 216.18 ng/ml for stages I, II, and III/IV, respectively; P = 0.016). Significantly higher plasma OPN levels were found in patients with a recurrence of HCC after resection, compared with those without recurrence (213.55 versus 153.70 ng/ml; P = 0.0013). A higher plasma OPN level was a leading independent prognostic factor for both overall survival (OS) and disease-free survival (DFS) in univariate and multivariate Cox models. This suggests that the preoperative plasma OPN level can be used as a predictive marker for HCC recurrence and may be helpful to assess the prognosis of patients with HCC after surgery.