Abstract: To investigate the protein expression of the membrane cytoskeleton cross linker protein (Ezrin), focal adhesion kinase ( FAK ), and phosphates and tensin homolog deleted on chromosome ten ( PTEN ) in  hepatocellular carcinoma (HCC) and determine their relationships. Methods: The expression profiles of Ezrin, FAK, and PTEN in 20 cases of normal liver tissues, 50 cases of HCC, and adjacent hepatic tissues were investigated in situ via SP  immunohistochemistry ( IHC ). The relationship between the expression profile and the biological behavior of HCC development and invasion was also analyzed. Results: The protein expression levels of Ezrin and FAK were significantly higher in HCC than in normal liver tissues ( P < 0.05 and P < 0.01, respectively ). At a high Ezrin concentration, an FAK expression level   was observed in 33 ( 66.0% ) HCC and 24 ( 48.0% ) normal cases . The strong expression of Ezrin ( P < 0.05 ) and FAK ( P < 0.01 ) were significantly correlated with histological grade, vascular invasion, and HCC satellite lesions. On the other hand, in 32 of 50 cases ( 64.0% ), a significantly lower PTEN level was found in the HCC tissue compared with those of adjacent hepatic tissues and normal liver tissues ( P < 0.01 ). No correlation between histological grade and liver cirrhosis was observed, even though the expression level of FAK was associated with vascular invasion and satellite lesions ( P < 0.05 or P < 0.01 ). Furthermore, no correlation between the Ezrin, FAK, and PTEN expression levels and patient age, gender, and tumor size was observed ( P > 0.05 ). A significant positive relationship was found between Ezrin and FAK expressions ( r = 0.445, P = 0.001 ), and an inverse correlation was detected between the expression of Ezrin and PTEN ( r = -0.475, P = 0.001 ) and FAK and PTEN ( r = -0.364, P = 0.009 ). Conclusion: Further studies need to be conducted to fully understand the strong expression of Ezrin and FAK, the weak expression of PTEN, and the underlying mechanism of HCC invasion and metastasis. In addition, a novel association between the abnormal expression of Ezrin, PTEN, and FAK and hepatocarcinogenesis possibly exists.