Abstract Background Early detection of small HCC and differentiation between HCC from AC metastatic to the liver is very essential for surgical pathologists, due to different treatment modalities. Immunohistochemistry plays a very important role in such conditions. In our study, we aimed to identify the diagnostic benefits of Arginase-1, FTCD& MOC-31 in the early detection of HCC in normal or cirrhotic liver, differentiation between HCC and metastatic ACs to the liver, and for early detection of small micrometastases from ACs to liver. Materials and Methods We included 20 samples from liver cirrhosis, 10 samples from normal liver tissue, 30 samples from primary HCCs in the liver, and 30 samples frommetastatic ACs to the liver.We have evaluated Arginase-1, FTCD, andMOC-31 expression using immunohistochemistry. Results The sensitivity of Arginase-1 expression in differentiation between HCC and metastatic carcinoma was 93.3% and the specificity was 93.3%. The sensitivity of FTCD expression in differentiation between HCC and normal or cirrhotic liver and early detection of welldifferentiated HCC was 90% and the specificity was 86.7%. The sensitivity of MOC-31 expression in differentiation between HCC and metastatic carcinoma was 90% and the specificity was 90%. The sensitivity of combination of panel of Arginase 1 + FTCD + MOC 31 expression in differentiation between HCC, metastatic carcinoma, and normal and cirrhotic liver was 93.3% and the specificity was 93.3%. Conclusions The combination of Arginase 1 + FTCD + MOC 31 expression was helpful in diagnosing most cases of HCC and metastatic carcinoma with high sensitivity and specificity.