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The prognosis of hepatocellular carcinoma (HCC) is poor and current therapies are largely ineffective. Transcatheter arterial chemoembolization is a standard treatment option for patients with unresectable HCC, especially when combined with other therapies. We report a 62-year-old male with huge HCC. The patient was first treated with adenovirus-mediated wild-type p53 gene (Ad-p53, gendicine) combined with oxaliplatin (200 mg) and transcatheter arterial chemoembolization or transcatheter arterial chemotherapy for two cycles. Review showed tumor shrinkage and a decrease in α-fetoprotein. Oxaliplatin was stopped because of side effects. Then the patient was treated with a tumor feeding arterial injection of Ad-p53 (1×1012 viral particles) twice and Ad-p53 (1×1012 viral particles) followed by 5-fluorouracil (500–750 mg) six times through port-catheter system. We observed marked tumor shrinkage and sustained normal α-fetoprotein and liver function during a 614-day follow-up period.