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Objective: The aim of this study was to investigate the expressions of CD147 and CK19 in hepatocellular carcinoma (HCC) and their clinical significance. Methods: The expressions of CD147 and CK19 were determined by tissue microarray and immunohistochemistry (IHC) in 272 cases of HCC and 81 cases of adjacent tumorous tissue. Results: The positive expression of CD147 in HCC and adjacent tumorous tissue was 73.53% (200/272) and 13.58% (11/81) with significant difference (P 0.05). Among the patients of positive expression of CD147, the median replacing time and overall survival were 13 and 24 months, lower than 48 and 60 months in the patients of negative expression (P < 0.05). Among the patients of positive expression of CK19, the median replacing time and overall survival were 7 and 13 months, lower than 31 and 42 months in the patients of negative expression (P < 0.05). The expression of CD147 had no correlation with the expression of CK19 (r =0.061, P = 0.317). Conclusion: The positive of CD147 and CK19 closely correlate with the clinical prognosis of HCC, it may indicate poor prognosis of HCC.