There is no available effective systemic treatment for patients with advanced hepatocellular carcinoma (HCC) who are intolerant of sorafenib or who have disease that has progressed on sorafenib. In Phase I and II studies, tivantinib (ARQ 197), an oral inhibitor of MET, demonstrated promising antitumor activity in patients with HCC, both as monotherapy and in combination with sorafenib. A randomized Phase II trial in second-line HCC showed improved overall survival (hazard ratio: 0.38; p = 0.01) in patients with MET-high tumors, as demonstrated by immunohistochemistry, treated with tivantinib versus placebo. Here we present the treatment rationale and study design of the METIV-HCC Phase III study. This randomized, double-blind study will investigate tivantinib monotherapy as second-line treatment in patients with advanced, pretreated, MET-high HCC. Approximately 303 patients will be randomized 2:1 to tivantinib or placebo for the purpose of analyzing the primary end point. Tivantinib will be dosed at 120 mg twice daily, and treatment will continue until disease progression, unacceptable toxicity, patient or physician decision to discontinue, or death. The primary end point of this study is overall survival, while secondary end points include progression-free survival and safety. All patients will be tested for biomarkers. If the primary objective is achieved, this study will provide the first effective therapy for a biologically selected patient population in HCC.