Background: Hepatocellular carcinoma (HCC) is one of the most common malignancies and the third most common cause of death from cancer worldwide. Approximately, 80 to 90% of HCC occur in a cirrhotic liver. HCC is now a rather common malignancy in Egypt which usually develops on top of liver cirrhosis secondary to viral infection. Hepatitis C virus increases the risk of HCC in the Egyptian patients. Osteopontin (OPN) is a glycoprotein secreted by cells as osteoblasts, osteoclasts, activated macrophages and T cells. It is over expressed in a variety of human tumors, including carcinomas of stomach, breast, prostate, lung, colon, and liver. Plasma level of osteopontin may be a biomarker for HCC. Objective: This study aimed to evaluate plasma osteopontin (OPN) level and determine its sensitivity and specificity as a screening tool for detection of HCC patients. Subjects and Methods: Plasma OPN level was measured in 64 patients(Twenty two patients with non-cirrhotic HCV, twenty two with cirrhotic HCV and twenty HCC patients on top of chronic cirrhotic HCV)in addition to twenty healthy controls. Plasma OPN level using ELISA technique was done to all participants. Also, liver enzymes (AST) and (ALT), serum bilirubin, albumin, alpha-fetoprotein and blood hemoglobin (Hb) were done to all participants. Results: The mean plasma osteopontin (OPN) level significantly elevated in patients with HCC group than all groups. The sensitivity and specificity in detection of HCC were 100% and 97% respectively at cut off level of 270 ng/ml with accuracy 95%. Conclusion: Plasma OPN level can be used as a routine biomarker for clinical prediction of the recurrence, metastasis, and prognosis in patients with HCC.