AIM: Hepatocellular carcinoma (HCC) is a global health problem because of its increasing prevalence worldwide and its poor prognosis. In Egypt HCC incidence has increased sharply and nearly doubled over the last decade. The outcome of HCC depends mainly on its early diagnosis; therefore, new and specific markers for HCC are critically needed. Osteopontin (OPN) is a glycoprotein that overexpressed in HCC, and known to be an independent predictor of poor prognosis. The aim was to assess the value of OPN in Egyptian patients with HCC. METHODS: This study included 40 patients with HCC, 20 patients with liver cirrhosis and 20 healthy controls. For all groups, clinical data and image findings were studied; serum alpha-fetoprotein & OPN levels were detected by enzyme immunoassay (EIA) kit. Tumor characteristics were assessed including size, number and site. Tumor staging was done using Okuda, CLIP, VISUM and Tokyo staging systems. RESULTS: Serum OPN was significantly higher in HCC patients compared to cirrhotic patients and controls. The sensitivity and specificity in diagnosis of HCC were 92.5% and 85% respectively at cutoff of 239 ng/mL with 91.1% accuracy. OPN has a positive significant correlation with tumor number (p = 0.036), CLIP (p = 0.02), Tokyo (P = 0.03), and VISUM (P = 0.01) staging systems. CONCLUSION: OPN could be a useful diagnostic & prognostic marker for detection of HCC.