Tumor-associated antigens (TAAs) recognized by cellular and/or humoral effectors of the immune system are attractive targets for diagnostic and therapeutic approaches to human cancer. Different approaches can be used to comprehensively characterize and validate the identified TAA/anti-TAA systems, which are potential biomarkers in cancer immunodiagnosis. Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide. The high fatality rate of HCC within one year after its detection might be partly attributed to a lack of diagnostic methods that enable the early detection. Our previous studies have shown that novel autoantibodies can appear which are not detected prior to pre-malignant conditions during transition from chronic liver disease to HCC. The hypothesis we advance is the transition to malignancy can be associated with autoantibody response to certain cellular proteins that might have some role in tumorigenesis. We propose that the information that the cancer patient's immune system is conveying in the form of autoantibodies to tumor-associated antigens (TAAs) should be utilized to a greater extent in identifying early signs of tumorigenesis. In this review, we will focus on the important features of TAA and the possibility that autoantibodies to TAAs can be used as biomarkers in immunodiagnosis and prognosis of HCC.