Osteopontin (OPN) and epidermal growth factor receptor (EGFR) are important factors associated with tumor progression, invasion and metastasis in humans. The aim of this study was to assess the correlation of OPN and EGFR expression with hepatocellular carcinoma (HCC) progression. Expression of OPN and EGFR was assessed by immunohistochemistry in 100 HCC specimens. Immunostaining scores (0 to 400) were calculated from the percentage of cells (0 to 100) at each immunostaining intensity and the immunostaining intensity (0 to 4). The average immunostaining score for OPN was correlated with tumor grade (56.1 for grade I, 104.6 for grade II, and 141.2 for grade III; P = 0.023) and T stage (58.6 for stage T1, 85.9 for stage T2, 126.8 for stage T3, and 189.1 for stage T4; P = 0.029). Similarly, the average immunostaining score for EGFR was correlated with tumor grade (80.5 for grade I, 142.1 for grade II, 230.6 for grade III; P = 0.011) and T stage (96.4 for stage T1, 135.5 for stage T2, 221.3 for stage T3, and 261.4 for stage T4; P = 0.026). In addition, OPN and EGFR immunostaining scores were also correlated with M, N, and AJCC stages. In conclusion, higher expression of OPN and EGFR is significantly associated with advanced histological grades, advanced pathological stages and poorer survival rates in HCC. OPN and EGFR may be used as novel biomarkers for diagnosis or monitoring of progression of hepatocellular carcinoma.