Hepatocellular carcinoma (HCC) is one of the most commoncancers worldwide. Detecting tumor markers in human serum is the mosteffective method in diagnosing HCC as it is convenient, inexpensive andaccurate.Annexin A2 (ANXA2) is a 36 kDa calcium-dependentphospholipid-binding protein that is located on the surface of mosteukaryotic cells. ANXA2 is involved in several biological processes,including anti-inflammatory effects, Ca2+-dependent exocytosis, immuneresponses, Ca2+ transport and phospholipase A2 regulation.Follistatin (FST) is a glycoprotein expressed in most organs, whichinteracts with activins or other members of the transforming growthfactor beta family. The aim of the study is to evaluate serum Annexin A2 andFollistatin as diagnostic serological markers for early detection of HCC. This study was conducted on 50 newly diagnosed patients withhepatocellular carcinoma, 30 post HCV/HBV patients, and 20volunteering apparently healthy individuals as controls. ANXA2 andFollistatin were measured in their sera by ELISA method. Annexin A2 was higher in the sera of HCC patients compared tothe hepatitis and the normal control groups at a P-value <0.001 each. It showed a sensitivity of 100% and a specificity of 84% compared to AFPthat showed a sensitivity of 82% and a specificity of 88%. Follistatinresults showed that it was higher in the sera of HCC patients compared tothe normal control group at a P-value <0.001, but when comparedbetween HCC and hepatitis groups it showed no significant results (Pvalue= 0.800). It showed a sensitivity and specificity of 66%. Annexin A2 is a promising biomarker for early diagnosis of HCCwhile Follistatin cannot differentiate between HCC and hepatitis patients