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Background: Osteopontin is an important tumor marker, since it presents as an immobilized extracellular matrix molecule in addition to present as a secreted form in body fluids involving plasma. Osteopontin levels in the plasma were found to be significantly higher in Hepatocellular Carcinoma (HCC) patients than in healthy control individuals and also higher than in patients with chronic liver diseases. Aim of Study:The aim of the present study is to evaluate the role of plasma OPN level as potential markers of HCC among HCV infected patients, compared to AFP. Also, its relationship with clinicopathological features of HCC patients.Study Design: This is a retrospective case control study. Subjects and Methods:The study included 100 adult subjects; they were classified in to 4 groups: Group 1: It included 30 apparently healthy individuals (control group). Group 2: It included 30 patients with HCV positive chronic hepatitis. Group 3: It included 20 patients with HCV positive liver cirrhosis without HCC. Group 4: It included 20 patients with HCV positive liver cirrhosis and HCC. Serum Osteopontin was measured by Enzyme-Linked Immunosorbent Assay ELISA. Results:The mean OPN level was (33.1 ± 16.4) ng/ml, (27.8± 13.8) ng/ml, (92.87 ± 18.5) ng/ml and (232.13 ±59.7) ng/ml for control, HCV, cirrhosis and HCC groups respectively, p-value=0.0010 and there were highly statistical significant differences between the four groups ( p<0.001). The mean AFP level was (4.6±2.4) ng/ml, (8.01 ±2.76) ng/ml, (24.8±25.9) ng/ml and (639±2226.8) ng/ml for control, HCV, cirrhosis and HCC groups respectively, p-value=0.0014 and there were highly statistical significant differences between the four groups (p<0.001). Conclusion:OPN can be used for diagnosis of HCC and differentiation between HCC and CLD, OPN has higher sensitivity and specificity than AFP and can be used for early diagnosis. Combination of OPN wih AFP has increased both sensitivity and specificity for detection of HCC.