Background. The role of serum ␣-fetoprotein (AFP) as a marker for treatment response in patients with hepatocellular carcinoma (HCC) receiving systemic therapy is poorly defined.Methods. A retrospective study was performed on patients with advanced HCC enrolled in five phase II clinical trials. Serum AFP was prospectively collected at baseline and at different time points through treatment in parallel with radiologic response and clinical outcome. Patients were separated into three groups based on a 50% change in serum AFP from baseline. Overall survival (OS), progression-free survival (PFS), and radiologic responses were compared between groups using log-rank and Wilcoxon tests.Results. Of 144 patients, 107 met the eligibility criteria. Eighteen patients experienced a >50% AFP decline, 57 patients had a >50% AFP increase, and 32 patients had a