Fifty patients with advanced hepatocellular carcinoma (HCC) were treated with sorafenib. In 25 of the patients, serum levels of protein induced by vitamin K absence or antagonist II (PIVKA-II) were evaluated at two time points (pretreatment and within 2 weeks from initial treatment). The time to progression in the "PIVKA-II-elevated group" (PIVKA-II more than two times pretreatment levels) was significantly longer than that in the "non-elevated group" (10.0 months [95%CI: 8.5-11.5] vs 5.7 months [95%CI: 3.3-8.1]; p=0.0296). It has been reported that hypoxia induces PIVKA-II in HCC cells. HCC treated with sorafenib are exposed to hypoxia caused by an antiangiogenic effect. Therefore, serum levels of PIVKA-II are a surrogate marker of tissue hypoxia and accordingly a predictive marker of treatment response by sorafenib.