Abstract: With the application of FOLFOX regimen (oxaliplatin, fluorouracil, and leucovorin) in hepatic arterial perfusion (HAIC), chemotherapy has shown a higher value in the comprehensive treatment of hepatocellular carcinoma. Especially in the era of integration of targeted therapy and immunotherapy, the FOLFOX‑HAIC, combined with immunotherapy and targeted therapy, further improves antitumor effect. The FOLFOX systemic chemotherapy combined with immunotherapy and targeted therapy scheme explored by the authors has achieved similar effects to triple therapy. Advanced hepatocellular carcinoma exhibits systemic disease characteristics, and systemic chemotherapy combined with targeted and immunotherapy has achieved higher disease control rates in the initial exploration. The mechanism may be that systemic chemotherapy changes the overall immune micro-environment of tumors, transforming the immune microenvironment from immunosuppressive to immune supportive, thereby better enhancing the efficacy of immunotherapy. The optimal regimen of systemic chemotherapy in comprehensive treatment may be obtained from the phase 3 study and basic studies in the future, which will be more efficient, safe and economical in the treatment of advanced hepatocellular carcinoma.