Hepatocellular carcinoma (HCC) is one of the most common types of malignant tumor. It is usually asymptomatic in the early stages and tends to be intravascularly and intrabiliary invasive. Therefore, most patients present with incurable disease at the time of detection and early diagnosis of HCC is critical for a good prognosis. The imaging-based diagnosis of small tumors is relatively inaccurate, as cirrhotic and dysplastic nodules mimic HCC radiologically. The availability of a suitable serological marker to distinguish between HCC and benign liver lesions would, therefore, be very useful for early diagnosis. The only serological marker currently widely used for the diagnosis of HCC is alphafetoprotein (AFP). However, the sensitivity of this marker is limited (41-65%). Given the high heterogeneity of HCC, it is currently thought that an optimal serological test for HCC will be based on the simultaneous measurement of two or three highly specific serological markers.Several laboratories have recently reported that glypican-3 (GPC3), a membrane-bound proteoglycan, is expressed by a large proportion of HCCs, but is undetectable in normal hepatocytes and non-malignant liver disease. Furthermore, various studies demonstrated that GPC3 could be used as a serological test for the diagnosis of patients with HCC. Although the specificity of the test was very high in the context of a population with chronic liver disease, the sensitivity was limited (within the same range as AFP). Interestingly, in most cases, elevated GPC3 values did not correlate with elevated AFP values. As a consequence, the serological level of at least one of the two markers was elevated in a large majority of HCC patients. These results suggest that the sensitivity of the diagnostic test can be significantly improved without compromising specificity with the simultaneous measurement of both GPC3 and AFP.