Glypican-3 (GPC3) mRNA and protein are expressed in >80% of human hepatocellular carcinomas (HCC) but not in normal tissues except for placenta and fetal liver. The oncofetal antigen GPC3 is a glycosylphosphatidyl inositol-anchored membrane protein and may be secreted. It is a novel tumor marker for human HCC: GPC3 protein was present in sera from 40-50% of HCC patients, but was not detected in sera from patients with liver cirrhosis or chronic hepatitis, or in sera from healthy individuals. alpha-Fetoprotein (AFP) and PIVKA-II (protein induced by vitamin K absence or antagonist-II), are well known major tumor markers for HCC. Generally, AFP shows high positivity for HCC but also high false-positivity in detection assays. Lens culinaris agglutinin-reactive fraction of alpha-fetoprotein (AFP-L3) is a recently described marker of HCC. Detection of AFP-L3 shows a much higher specificity than AFP, but a lower sensitivity. On the other hand, detection of PIVKA-II shows a lower false-positivity, but is not always sensitive enough to detect low levels secreted by small HCCs. There was no correlation between the three tumor markers, AFP, PIVKA-II, and GPC3 in terms of their presence in HCC cells. All three tumor markers showed similar positivity in patients with HCC, detecting 80% of patients with the disease. GPC3 is also a novel tumor marker for the diagnosis of human melanoma, especially in the early stages of the disease. Expression of GPC3 mRNA and protein was evident in tumor cells from >80% of patients with melanoma and melanocytic nevus, which is a common benign lesion. GPC3 protein was detected in sera from 40% (36/91) of melanoma patients, but not in sera from those with large congenital melanocytic nevus, or from healthy donors. Surprisingly, we detected serum GPC3 even in patients with stage 0, in situ melanoma. The positive detection rate of serum GPC3 at stage 0, I, and II (44.4%, 40.0%, 47.6%, respectively) was significantly higher than that of 5-S-cysteinyldopa, a well known tumor marker for melanoma (0.0%, 8.0%, and 10.0%, respectively). Interestingly, GPC3 was highly immunogenic in mice and elicited effective anti-tumor immunity with no evidence of autoimmunity. Thus, GPC3 is useful for diagnosis of HCC and melanoma and may also have a role in immunotherapy or tumor prevention. However, studies in humans are warranted.