Advanced stage primary hepatocellular carcinoma (HCC) accounts for more than half of all cases worldwide. Poor prognosis is mainly attributed to intrahepatic tumor burden caused by high-risk factors, including Vp4-portal vein tumor thrombosis or tumor occupancy of >50% of the liver. In 2020, the combination of a VEGF/PD-L1 blocker was superior to a single tyrosine kinase inhibitor and associated with a median overall survival of 19.2 months. However, overall survival dramatically declined from 19.2 months to 7.6 months for patients with high-risk factors. In this present study, the FOHAIC-1 trial, interventional hepatic arterial infusion chemotherapy of FOLFOX (HAIC-FO) showed favorable survival outcomes in patients with high-risk advanced HCC. Compared with a tyrosine kinase inhibitor, in the high-risk subgroup, HAIC-FO achieved an overall survival of 10.8 months (vs. 5.7 months, hazard ratio 0.343, 95% confidence interval, 0.219–0.538). This study also observed disease downstaging in 16 (16/130) patients who received HAIC-FO; 15 (93.8%) patients received curative or regional treatments afterward. Therefore, for advanced HCC with localized high-risk factors, the clinical efficacy of HAIC-FO is significant and may be a better option than systemic therapies.