Background: Hepatocellular carcinoma (HCC) is a major public health problem, representing the fifth most common malignant tumor worldwide, and the third most common cause of cancer related deaths. In Egypt, HCC is the second most common malignant tumor for males after cancer urinary bladder and the fifth for females. It has been recognized that AFP has a low sensitivity in detection of HCC, and that AFP level often increases in the absence of HCC. Thus the identification of novel biochemical markers for HCC remains an important goal for many laboratories around the world. Cyclase-associated protein 2 (CAP2) has recently been suggested to be a candidate biomarker for hepatocellular carcinoma. We aim to investigate the application of CAP2 as a novel biomarker for HCC patients. Methods: The CAP2 and AFP plasma levels were analyzed by enzyme-linked-immunosorbent assay (ELISA) in 45 HCC patients, 20 cirrhotic patients and 20 normal invididuals. Their correlation with HCC tumor behavior, diagnostic sensitivity, specificity and accuracy were analyzed. Results: The results showed that both CAP2 and AFP plasma levels in HCC patients were significantly elevated when compared to cirrhosis and controls. CAP2 levels in HCC patients correlate well with serum total Bilirubin, PT and INR but not with patient's age, gender and plasma AFP. CAP2 had better sensitivity as compared to AFP (80% vs. 66.67%) for HCC. Conclusion: The development of HCC in patients with liver cirrhosis might be predicted by an increasing plasma level of CAP2 and plasma CAP2 might be useful diagnostic biomarker of HCC patients with chronic liver disease.