Rationale: Hepatocellular carcinoma (HCC) is a highly invasive cancer associated with vascular invasion. The survival of advanced HCC is very poor. In this case study, we describe the efficacy and safety of apatinib in patient with advanced HCC as the first-line therapy. Patient concerns: A 46-year-old male complained of abdominal distention and pain for half a month. Diagnoses: HCC patient with portal vein and inferior vena cava tumor thrombus. Interventions: The apatinib alone was used as first-line therapy. Outcomes: Intrahepatic tumors, portal vein, and inferior vena cava tumor thrombus were diminished. The patient achieved partial response (PR) soon after the treatment, and progression-free survival (PFS) was 12.5 months. During the entire process, the alpha-fetoprotein (AFP) continued to decrease. Lessons: Apatinib alone may be a safe and effective therapy for HCC patients with portal vein and inferior vena cava tumor thrombus. However, it is warranted further investigation in the future prospective randomized clinical studies.