Background: At present, there is no standard for the posterior treatment of hepatocellular carcinoma (HCC). This study isTo evaluate and compare the safety and efficacy of transcatheter arterial chemoembolization (TACE) combined with regorafenib and anti-PD-1 antibody with continued TACE combined with regorafenib in patients with HCC after the failure of second-line treatment with regorafenib.Methods: We enrolled patients with advanced HCC who were treated with sorafenib and sequential regorafenib. All patients were treated with TACE and found to have tumor progression in 2021. After tumor progression, patients were treated with TACE combined with regorafenib and PD-1 antibody or with continued TACE combined with regorafenib according to the wishes of the patient. Efficacy was evaluated after 1 month of treatment. The objective response rate (ORR), disease-control rate (DCR), and safety were evaluated according to adverse reactions of patients.Results: Nine patients were treated with TACE combined with regorafenib and PD-1 antibody, and the 9 patients continued to receive TACE combined with regorafenib. There was no significant difference in baseline data between the 2 groups. In the PD-1 group five patients achieved a partial response (PR), three achieved stable disease (SD), and one patient had progressive disease (PD) after 1 month of treatment. The ORR was 55.6% and the DCR was 88.9%. In the continued TACE-regorafenib group, four patients achieved PR, one achieved SD, and four patients achieved PD after 1 month of treatment, while the ORR was 44.4% and the DCR was 55.6%. There was a significant difference in the DCR between the two groups (P=0.012), while adverse events were similar in both.Conclusions: TACE combined with regorafenib and PD-1 antibody had a higher DCR and was more effective than continued TACE combined with regorafenib in patients with HCC who failed second-line treatment with regorafenib. However, PD-1 antibody therapy might increase the risk of death by causing an uncontrollable immune response. Given the risk of an immune response, patients may choose to continue TACE combined with regorafenib, given the similar ORR of the two treatments.